Endogenous opiates: 1991

Peptides,Vol. 13, pp. 1247-1287, 1992

0196-9781/92 $5.00 + .00 Copyright© 1992PergamonPressLtd.

Printed in the USA.

REVIEW

Endogenous Opiates: 1991 G A Y L E A. O L S O N , *l R I C H A R D D. O L S O N * A N D ABBA J. KASTIN*~':~

*Department of Psychology, University of New Orleans, New Orleans, LA 70148, tVeterans Affairs Medical Center, New Orleans, LA 70146, and ¢Tulane University School of Medicine, New Orleans, LA 70118 OLSON, G. A., R. D. OLSON AND A. J. KASTIN. Endogenousopiates:1991.PEPTIDES 13(6) 1247-1287; 1992.--This paper is the fourteenth installment of our annual review of research concerning the opiate system. It includes papers published during 1991 involvingthe behavioral, nonanalgesic,effects of the endogenous opiate peptides. The specifictopics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal and renal function; mental illnessand mood; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical-related activity; general activity and locomotion; sex, pregnancy, and development; immunological responses;and other behaviors. Stress Tolerance Dependence Eating Drinking A l c o h o l Depression Learning Cardiovascular responses Temperature Respiration E p i l e p s y A c t i v i t y Mental illness Sex Immunology Opiate Peptide

RESEARCH interest in the endogenous opiate peptides has continued to grow, with an emphasis on their involvement in the mediation of a variety of behaviors, including physiological ones. In 1991 this trend continued, but there still remain many mysteries in the answers to those questions. Little is yet known about the mechanisms used by the opiate system to modulate responses, although attempts to discover them have increased. This paper reviews work published in 1991 that investigated the behavioral and nonanalgesic, except stress-induced analgesic, activity of the opiate system. It is the fourteenth installment in our series of reviews that tracks the annual developments in the field. Since the word opioid is now used to refer to all drugs with morphine-like actions, rather than only to endogenous ones, as originally intended, there seems little point in its use. Current use makes no distinction between it and opiate, so we shall use the more commonly known term opiate. Activation of the opiate system by stress has continued to be of great interest, as it had from the start of work in the area. The type of stressor has broadened from the emphasis in early years on electric footshock and forced swims to include restraint, isolation, defeat, and extremes of temperature. Measures include not only analgesia, but cries of distress and cardiovascular responses. Interest in tolerance and dependence has increased recently, even though it had always been important. Strong emphasis is still placed on variables that affect their development and withdrawal from the opiates. Postulated mechanisms involve receptor subtypes, binding ait~nity, and interactions with other peptides and systems. There was less interest in 1991 in opiate mechanisms of eating and drinking, despite increased awareness of the possible role of the opiate system in eating disorders and

1Requests for reprints should be addressed to Gayle A. Olson. 1247

Memory Aggression

alcoholism; perhaps conflicting results in these areas contribute to the decreased interest. An even greater loss of interest in the opiate modulation of gastrointestinal and renal function occurred, possibly for the same reason. Similarly, in recent years less research has been conducted than previously on the potential involvement of the opiate system in mental illness. The early hopes that the opiate peptides might mediate schizophrenia have largely been dashed, and interest has focused on opiate contributions to depression, with somewhat better success. Research in the modulation of learning and memory, especially memory, has grown in recent years, although we are still unable to delineate it. Additional work has also looked at how the opiate system mediates reward, a more promising area. Interest in opiate involvement in cardiovascular responses has remained at a consistently high level for many years, although the focus has shifted from attempting to discover mechanisms of cardiovascular shock to the effects of opiates on heart rate and blood pressure, especially hypertension. The control of respiration and thermoregulation by the opiate system has received less attention in recent years, especially thermoregulation, probably because the opiates appear to have little physiological involvement in it. Interest in opiate mediation of seizures and neurological disturbances rebounded a little this past year, after several years of decline. There still continues to be hope that therapeutic value might result from discovery of mechanisms involved here, not only for seizure activity, but also for nerve damage and diseases like Alzheimer's and Parkinson's, although only a small degree of success has been observed. There was also renewed interest in how electrical-related behaviors might be controlled by the opiate system, and with ever-increasing sophistication in meth-

1248 ods, it can be expected to continue. Similarly, there was an increase in research on opiate involvement in general activity, as well as locomotion. Another set of areas that has received additional attention this year were sexual behavior and development, from prenatal stages to old age. The relation of the opiate system to immunological responses is still another field that is growing and will probably continue to do so, since interest in immunology continues to grow. Finally, there are a number of miscellaneous behaviors, such as social responses and activities that respond to cyclical forces, that continue to stimulate interest. STRESS It has been known for many years that some stressors induce analgesia and other responses that might be mediated by the endogenous opiate system, since these effects can be modified by opiate agonists or antagonists. Other stressors, even if similar to the opiate ones, are unaffected by opiate blockade and thus probably do not involve the opiate system. Of interest have been the variables that invoke opiate mediation and how they interact with other systems that come into play when the organism is stressed. One of the most frequently studied stressors has been electric footshock in animals, and interest in it persisted in 1991. An example of similar stimuli producing opiate or nonopiate responses was found in the placement of the shock. Shock to the front paws induced opiate analgesia, but hind-paw shock produced nonopiate analgesia (391). Similarly, a brief shock in a distinctive environment induced nonopiate analgesia, but conditioned analgesia produced by later returning the animal to that environment, without any shocks, was opiate in nature, since it was reversed by naltrexone (305,327). The amount of training was critical, though, since with few training trials the conditioned analgesia was opiate, but with extended training it was not responsive to naltrexone. Numerous studies reported opiate-mediated analgesia after shock (219,279,280,305,327,391), since the antinociception was eliminated by administration of naloxone (391), naltrexone (219,305,327), or the endogenous antiopiate Tyr-MIF-1 (279,280), although other variables also played a role. Pretreatment with dopamine antagonists, for example, potentiated the shock-induced analgesia and inhibited Tyr-MIF- I's suppression of it (279), indicating activation of the dopamine receptors in this response. Similarly, conditioned suppression of motility, which occurred when rats were placed in a cage in which they had previously been shocked, was accompanied by a decrease in dopamine turnover, both effects being attenuated by [D-AIa2D-Met]enkephalinamide (DAMEA). This inhibition was antagonized by naloxone, suggesting an interaction between the opiate and dopamine systems for this response (242). Conversely, neither the H~ receptor antagonist chlorpheniramine maleate nor the H2 receptor antagonist cimetidine altered shock-induced analgesia or its reversal by Tyr-MIF-I (280). Pertussis toxin inhibited opiate-mediated but not nonopiate shock-induced antinociception, suggesting that pertussis-sensitive G-proteins are an essential transduction step needed to produce the molecular events underlying this opiate effect of shock (391). Both food deprivation and the diurnal cycle also influence shockinduced analgesia, with deprivation facilitating the hypoalgesia, which was greatest during the late part of the light phase (219). Physiological support for the concept that shock-induced behaviors, including conditioned analgesia, can be mediated by changes in the endogenous opiate system was provided by the finding that concentration of immunoreactive/%endorphin increased in the periaqueductal gray (PAG) and pituitary of rats after inescapable shock, and reexposure to the chamber in which shocks occurred produced a decrease in the peptide (137).

OLSON, OLSON AND KASTIN Similarly, restraint stress has been shown to increase opiate peptide content in serum (314) and pituitary (315) but decrease it in the hypothalamus in a naltrexone-reversible way in some animals (512). Other studies, with more prolonged immobilization, however, have reported no change in hypothalamic concentrations of/~-endorphin (314,315). Despite the finding that plasma Met-enkephalin was unchanged by restraint, the procedure did alter heart rate, producing tachycardia in normal rats and bradycardia in hypophysectomized rats, indicating some pituitary modulation of this response (36). Likewise, during chronic restraint, secretion ofgonadotropins was inhibited, and naltrexone did not alter this suppression, suggesting that the endogenous opiates did not mediate the response, although the opiates were active during acute stress (170). Behaviorally, besides the cardiovascular responses, restraint produced analgesia, which was opiate when done both in the cold ( l 17) and at room temperature (439). It also altered seizure susceptibility, with the direction of the effect depending on the method of seizure induction ( l 17). Brief restraint, but not that of longer duration, significantly suppressed subsequent locomotion, although naltrexone potentiated the weak effect of the longer duration of restraint, thereby reducing activity after it as well. Furthermore, pretreatment with ethanol eliminated the suppression induced by brief restraint in a naltrexone-reversible way (524), indicating mediation of the response by the endogenous opiate system. Pregnant rats exposed to immobilization reduced their weight gain but increased the birth weight of their pups, and the prenatally stressed pups learned more rapidly and had more exploratory behavior than nonstressed controls, suggesting that activation of the opiate system during gestation facilitates development of the central nervous system (CNS) of the pups (506). Another stressor of rat pups frequently studied is isolation from iittermates and/or mothers, with ultrasonic vocalization of the pups being the index of stress. Mu agonists, including morphine (251,566) and Tyr-D-Ala-Gly-NMe-Phe-Gly-ol (DAMGO) (83), and delta agonists, such as [D-Pen2.~]enkephalin (DPDPE) (83), tend to reduce the rate of the calls, but the kappa agonist U-50,488H (83) and the opiate antagonists naloxone (251) and naltrexone (84) increased the rate of calling, indicating opiate involvement in the distress response. Ultrasonic vocalizations were reduced by the drinking of a preferred flavor, such as saccharin or saline solutions, and this suppression was reversed by naltrexone, so that the endogenous opiate system might have mediated the response (250). The older the rat pup, the greater the effect of DPDPE, since there is a growth in the delta receptor population in the early days of development (83). Prenatal exposure to ethanol reduced the modulation of the vocalizations by the opiates and inhibited isolation-induced analgesia, suggesting that ethanol suppressed the development of the opiate system in the rats, at least for social stimuli (251). Further support for alteration of the opiate system by isolation was reported in the finding that proenkephalin mRNA decreased in the brains of rats isolated for up to 2 weeks, although the level returned to normal after 28 days of isolation. The rats became progressively more aggressive with the duration of the stress and had decreased locomotor activity throughout, however, so that the proenkephalin mRNA only correlated with behavior in the early stages of isolation. Nevertheless, this demonstrates that a physically noninvasive stressor can alter brain neurochemistry, which may represent a mechanism of brain to help adapt or protect from deleterious effects of chronic psychological stress (19). Another psychological stressor studied was exposure of rats to displays of other rats being shocked, but concentrations of corticosterone and the norepinephrine metabolite MHPG-SO4 were not affected by either morphine or naloxone (509), indi-

OPIATES: 1991 cating lack of opiate control for this response. It is not clear whether the kind of stressor or the specific measure used is responsible for the differential results. Another social stimulus that is used to study opiate mediation of stress is placement of an intruder animal in the home cage of another one, with the resident animal attacking the intruder. Defeat increased concentrations of Met-enkephalin in the PAG (94) and typically produced in the defeated intruder analgesia that was reduced by opiate antagonists, including naloxone (246) and FMRFamide (246), and initially by naltrexone, or ICI154,129, but not after more than a week of chronic infusion. Opiate agonists, however, also suppressed defeat-induced analgesia, at least initially, and both agonists and antagonists modulated antinociception and inhibition of locomotor activity produced by conflict not resulting in defeat, indicating activation of and involvement of opiate receptors in the mediation of behavioral consequences of aggression and defeat (515). Other responses to conflict were also altered by the opiates, including ultrasonic vocalization during the encounter (188), and tolerance to morphine-induced analgesia (353), but not to the discriminative stimulus (S D) properties of morphine nor to its suppressive effects on activity (353). Exposure of mice to cats for a short period produced an opiate antinociceptive response, but longer exposure resulted in a weak nonopiate analgesia, with sex differences such that the opiate analgesia was greater in males and the nonopiate one was stronger in females (244), indicating an interaction between the opiate system and the sex hormones. There was also a difference between wild and laboratory rats in their reaction to a predator cat, with the former displaying opiatesensitive responses and the former nonopiate ones. In the wild rats, morphine itself had opposite effects, with generalized enhancement of behavior, but inhibition of more specific responses to painful and tactile stimuli (59), indicating highly complex interactions between the opiate system, other systems, and experimental variables. Forced swimming may produce analgesia that is not reversed by naloxone (i 17,336,380,517), although some conditions, such as intermittent cold water swims, induce opiate analgesia that is facilitated by an enkephalinase inhibitor, which thus preserves the enkephalin. The increased antinociception is suppressed by naloxone (254,563) or the delta antagonists ICI 174,864 and naltrindole (563), further supporting the role of the opiate system in the response. Other delta ligands, including DALCE ([DAlaE,Leu5,Cysr]enkephalin) and/3-funaltrexamine, did not alter the analgesia of cold water swims, however, suggesting the possibility that some delta receptor subtypes are involved but not others (563). Swims in water at room temperature, but not warm water, induce analgesia that is naloxone sensitive, but temperature itself is not necessarily the determining factor, since histamine alters the analgesia in water at room temperature but not in warm water, suggesting that histamine is involved in the pathways mediating opiate antinociception for this response (380). Conversely, NMDA receptors are critical for nonopiate but not opiate swim-induced analgesia, since the NMDA antagonist MK-801 inhibits the analgesia in opiate receptor-deficient mice and since naloxone does not affect it, but both antagonists are necessary to block the analgesia in mice rich in opiate receptors (336). Exposure to a hot or cold floor resulted in analgesia, and repeated exposure to it produced conditioned hypoalgesia. The acquisition of the conditioned hypoalgesia was facilitated by naloxone (145,146,560) and was inhibited by morphine, especially in morphine-tolerant rats (560), suggesting that the opiate system might regulate the aversive properties of the stimuli in this situation. Learning was unaffected by yohimbine, clonidine, proprandol, and prazosin, indicating that the response was not

1249

mediated by the release and turnover of norepinephrine (146). Release of prolactin after exposure to a novel environment was apparently modulated by the opiate system in aged male rats, since the effect was reversed by naltrexone (71). Another aversive stimulus that produces some opiate-mediated effects is inflammatory pain. It causes a loss of body weight, hypophagia, and reduced mobility, all of which can be enhanced by a high dose but not a low dose of naloxone, suggesting involvement of the kappa but not mu receptors (354). Prolonged inflammatory pain induced the release of immunoreactive enkephalins but not i3-endorphin or dynorphin from rat hypothalamus, and the release of only the enkephalins was stimulated by corticotropin-releasing factor (CRF), suggesting CRF mediation of the opiate peptide release (468). Exposure to magnetic fields can affect nociception, presumably through modulation of the opiate system, since it attenuates both morphine-induced analgesia and responses to painful stimuli in land snails (Cepaea nemoralis), both in the laboratory (245) and in the natural environment (529). The magnetic fields can disrupt day-night rhythms of nociception as well (245), indicating that the magnetic fields apparently exert powerful influences on the opiate system. The stresses of surgery also appear to be mediated by the opiate peptides, or at least 13-endorphin, since concentrations of the peptide in plasma increase just before surgery (399,418,547) and remain high for 4 hours after surgery (547). The concentration of 13-endorphin correlated with blood pressure and heart rate but did not correlate with changes in anxiety before and after the surgery, so the peptide is not a good measure of emotional responses to the stressor (399). In infants after cesarian section, the increased concentrations ofl3-endorphin were negatively correlated with measures of respiration, demonstrating a release of the peptide in response to hypoxia associated with delivery (418). Immaturity in respiration, however, as measured by bouts of apnea, was not correlated with concentration of/3endorphin in neonates (297). Perinatal stress in general was associated with increased/~-endorphin, especially prematurity, but gender was also a factor, since being male was one of the best predictors of elevated concentrations of B-endorphin (297). There was no change in the amount of Met-enkephalin in the plasma with surgical stress, though, emphasizing the different precursors for it and ~-endorphin (547). A phenomenon experienced by scuba divers may be mediated, in part, by the opiate system. Submersion of divers in a state of neutral buoyancy for 20 minutes increased plasma concentrations of ~/-endorphin and was accompanied by reported feelings of euphoria, relaxation, and well-being. The increased B-endorphin was negatively correlated with diving experience and positively correlated with amount of air usage during submersion (520), suggesting that the rise occurred in response to the stress of submersion. This is more than just a response to diving pressure, however, since the mimicking of diving pressures in a hyperbaric chamber did not affect either plasma/3-endorphin or affective feelings (521). Thus, this mild stressor, like many more intense ones, can activate the opiate system to modulate responses to it. TOLERANCE AND DEPENDENCE Interest in the mechanisms and variables that affect the development of tolerance and dependence has continued to grow in recent years. The biological bases for tolerance and dependence are beginning to be delineated, including changes in the endogenous opiate system and other systems that accompany the phenomena. Much interest focuses on withdrawal and the information it provides about how dependence develops. There is

1250 also research on the more practical aspects of how to treat individuals who have become tolerant or dependent and what can be done to prevent this. Chronic administration of morphine is associated with specific changes in the endogenous opiate system, especially in the brain. Concentrations of fl-endorphin in the midbrain, pituitary, and hypothalamus decreased in morphine-dependent rats, and withdrawal produced subsequent changes that depended on the type of withdrawal. Protracted withdrawal, due to abstinence, further decreased pituitary/3-endorphin and lowered it in the amygdala and spinal cord as well, but naloxone-precipitated withdrawal increased the peptide in the corpus striatum, midbrain, cortex, and plasma, and decreased it in the hippocampus and pituitary (180). Similarly, concentrations of Met-enkephalin decreased in the pons, medulla, amygdala, hippocampus, and pituitary during chronic morphine and reacted differentially during different types of withdrawal. Protracted abstinence reduced Met-enkephalin in the spinal cord, amygdala, pons, medulla, midbrain, cortex, corpus striatum, and pituitary, but naioxone-precipitated withdrawal increased the enkephalin in the hypothalamus and corpus striatum and decreased it in the amygdala and pituitary (180). In another study, however, the concentration of Met-enkephalin in the lumbar and sacral spinal cord was unaffected by chronic morphine, but a challenge with naloxone increased it, although methodological variables might account for the differences (105). Both chronic morphine and U-50,488H decreased the concentration ofprodynorphin mRNA but not dynorphin A in the hypothalamus, hippocampus, and striatum, indicating that one of the changes in the endogenous opiate system that occurs with chronic exposure to opiates is the regulation of gene expression (436). There is no doubt that chronic morphine produces tolerance and dependence, and this occurs with other opiate peptides as well. Much of the research focused on receptor subtype specificity. In 1991 there were behavioral demonstrations of tolerance and dependence to chronic administration of the mu agonist DAMGO (171,343), the delta agonists DPDPE (171,343,477) and [D-Ala2]deltorphin II (343), [D-Ser2,LeuS]enkephalin-Thr6 (DSLET) (477) and [D-Ala-D-Leu]enkephalin (DADLE) (435), which are only slightly selective for delta over mu (292), the kappa agonist dynorphin and some but not all analogs of it (360), and even tramol, an opiate analgesic with low affinity for the mu, kappa, and delta receptor subtypes (249). The mixed agonist/antagonist butorphanol also produced dependence (211), as did the enkephalinase inhibitor thiorphan when given chronically (66). Although daily administration of the kappa agonist U-50,488H produced tolerance to its analgesic effect (52), neither it nor U-62,066E produced tolerance to its antitussive action (232), indicating differential activity of the peptides on different measures. Cross-tolerance between morphine and other agonists was studied, with no cross-tolerance developing between the kappa agonist U-50,488H and morphine (53,292), but coadministration of the two, when either was administered at the spinal level, suppressed the development of tolerance to morphine, suggesting that kappa receptors in this area, but not those located systemically or in the brain, are involved in morphine tolerance (508). Tolerance to morphine appears to be both supraspinal for mu receptors and spinal for mu and delta receptors, since concurrent intracerebroventricular (ICV) and intrathecal (IT) administration of the mu agonist fentanyl or the weak delta agonist DADLE produces differential effects in nontolerant and tolerant rats (435). In the guinea pig ileum preparation from morphine-tolerant rats, there was cross-tolerance to the mu agonist DAMGO and the weak delta agonists DADLE and DSLET, with a biphasic response indicating first delta mediation and then mu mediation

OLSON, OLSON AND KASTIN to the highly selective delta agonist DPDPE (292). The delta antagonist natrindole markedly suppressed development of morphine tolerance and dependence (3), further supporting a role for the delta receptors. Tests of cross-tolerance among delta ligands have led to the conclusion that there is more than one kind of delta receptor. [D-Pen2'5]Enkephalin produced cross-tolerance to DADLE (477) but not to [D-Ala2]deltorphin II (343) or DSLET, and DSLET was cross-tolerant with DPDPE but not DADLE (477). There was probably no involvement of the mu receptors in these responses, since none of the delta agonists was cross-tolerant to DAMGO (343,477) and since some of the rats tested had been pretreated with fl-funaltrexamine to alkylate the mu receptors (477). One delta subtype appears to interact with DADLE and DPDPE, and another with DSLET (477). Receptor specificity during tolerance and dependence probably has been demonstrated most definitively in receptor binding studies, which showed alterations in binding with chronic administration of an agonist. In general, downregulation of receptors for their specific ligand was reported in 1991, with some cross-tolerance over receptor subtypes. Chronic administration of mu agonists decreased mu receptor binding (38,49-51), but had no effect on affinity for those receptors (38). There was no effect on binding of delta or kappa receptors (49-51 ). There was, however, a report in 1991 of increased mu binding and delta density in striatal slices from morphine-dependent rats (4), indicating that there might simply be a change, rather than a decrease, in binding that is associated with tolerance and dependence. In previous years there also have been reports of upregulation. Chronic kappa administration produced downregulation of both kappa and delta receptors, but not mu receptors, and chronic administration of a delta agonist was associated with downregulation of delta receptors primarily (49). Other studies have suggested that tolerance to morphine might not be due to a desensitization of mu receptors, but to the fact that morphine is acting against an upregulated signal transduction mechanism (540). Those mechanisms may include enhanced expression or modification of D, receptors, G-proteins, and calcium channels in central neurons on which mu receptors are present (119,453,539). Tolerance is associated with increased adenylate cyclase activity (97,119,541), which is correlated with changes in G-proteins ( 119,541 ). There seems to be some uncoupling of receptors from G-proteins normally associated with them, thereby resulting in a loss of capacity of proteins to exchange GDP for GTP (97), suggesting that tolerance to morphine might be caused by the fact that the opiate is acting against an upregulated signal transduction mechanism, rather than by desensitization of central mu receptors (119). The opiate agonists DPDPE and DAMGO also stimulate corticosterone, suggesting both mu and delta involvement in the regulation of the hypothalamic-pituitaryadrenocortical (HPA) axis during tolerance. Since 2-deoxy-Dgalactose, but not 2-deoxy-D-glucose or 6-deoxy-D-galactose, enhanced the development of tolerance, it is possible that the former changed the binding characteristics of morphine or modified certain glycoproteins that could be of regulatory importance in opiate-mediated events, thus providing a possible basis for tolerance (424). Chronic morphine has been shown to increase dopamine turnover in the cortex and striatum of the rat (390) and to increase dopamine and its metabolites in the nucleus accumbens, indicating increased release of dopamine due to the tolerance to morphine (405), suggesting a possible mechanism for the tolerance. Dopamine release in the nucleus accumbens was also mediated by the administration of mu or kappa ligands (479), dopamine concentrations in the brain being suppressed during

OPIATES: 1991 naloxone-precipitated withdrawal (6,405), and p-chloramphetamine, which is known to affect dopamine, inhibited some naloxone-precipitated behaviors (286), providing further support for the role of dopamine in opiate tolerance and dependence. There was, however, no change in sensitivity to dopamine, since its ability to inhibit the firing of nucleus accumbens cells was unaffected by chronic treatment with morphine. The discrepancy may relate to the D~ and D2 subtypes of receptors, although this idea is speculative (226). The D~ receptors were implicated in the abstinence phenomenon after tolerance to kappa agonists, however, since the binding of the D~ antagonist SCH 23390 was increased with removal of U-50,488H (50). It also seems likely that excitatory amino acids (EAAs) and NMDA in particular are involved in some way in tolerance, since the NMDA antagonist MK-801 interfered with the development of tolerance to morphine (335,525,527). MK-801 acted in the absence of the learning of cues associated with the drug environment since it is known to inhibit learning, suggesting that it acts directly on neural changes, specifically attenuating the ability of morphine to increase striatal prodynorphin (527). Furthermore, MK-801 does not affect morphine analgesia directly, suggesting that it works in tolerance by antagonizing EAAs (335). There are contradictory findings about the role of EAAs in naloxone-precipitated withdrawal, however, with MK-801 suppressing behavioral signs of withdrawal (338,421), but other EAA antagonists intensifying the effect of naloxone (24). Not surprisingly, doses of naloxone and of the EAA antagonists, as well as the extent of dependence, were important factors. Thus, it appears that the EAAs are involved in opiate tolerance and possibly dependence. An antiopiate neuropeptide that appears to contribute to morphine tolerance and dependence is neuropeptide FF. Antiserum to it restored responses to morphine in tolerant rats to nontolerant levels but produced no effect in nontolerant rats (284,285). In addition, the peptide induced in dependent animals abstinence signs similar to those of naloxone, and a neuropeptide FF antagonist attenuated the signs induced by neuropeptide FF or naloxone (329). The development of tolerance to morphine was blocked when morphine was coadministered with cyclo(LeuGly) (77) or CCK antagonists (252). Perhaps more attention should be given to the antiopiate peptides known to exist for a dozen years. The sympathomimetics ephedrine and phenylpropanolamine enhanced the development of tolerance to morphine if administered during its induction phase (110), further indicating the complexity of the phenomenon. Clonidine abolished many of the symptoms of withdrawal (109,192,405), and yohimbine inhibited many of the behavioral signs (511), but not the hemodynamic (109) or the nociceptive responses (511). Similarly, benzodiazepines (328), calcium channel blockers (35), substance P (276), and 4-DAMP, an M2 muscarinic receptor antagonist, but not the M~ antagonist (76), reduce symptoms of withdrawal. The serotonin antagonists ondansetron and MD1 72222, however, had no effect on withdrawal, except attenuation of weight loss (204), although pchloramphetamine, which is known to affect serotonin, inhibited some naloxone-precipitated behaviors but not others (286). There are, therefore, multifarious interactions between the opiate system and other systems in dependence. It appears that chronic administration of an opiate is not necessary to produce tolerance, since there have been a number of demonstrations of acute tolerance after a single injection of morphine (262,263,283,319,405,451), with little difference between the effects of acute and chronic induction. Pretreatment with naltrexone did not alter the development of either chronic or acute tolerance in mice, although it did produce a supersensitivity to morphine analgesia and receptor upregulation (319).

1251 Chronic and acute morphine caused similar amounts o f i n ~ of dopamine in the rat nucleus accumbens, and both were mediated in clonidine, which eliminated the effects of withdrawal (405). Hamsters, too, showed both acute and chronic tolerance to morphine (451). Although the typical test for tolerance is a reduction in effectiveness of the peptide in relief of pain, other measures have been used, sometimes with opposite results, as indicated above. Tolerance to botlx morphine's suppression of responding and SD effects was demonstrated in rats (575) and pigeons (536) after repeated administration of morphine, so that a larger dose of the agonist was needed to produce the same effect. Other learning tasks have been used to show tolerance. Chronic administration of morphine induced less impairment of memory of a spatial learning task than acute administration of morphine (347) and produced a loss of its analgesic effect, thus reducing escape reaction times over days (579), indicating that tolerance had developed with its daily injection. After chronic presentation, morphine also lost its ability to suppress activity of oxytocin neurons in the rat supraoptic nucleus (413) and of thalamic ventrobasal neurons in the rat (248). There were also changes in cyclic GMP-phosphodiesterase activity with chronic morphine that correlated with the development of morphine-induced analgesia, catalepsy, respiratory depression, and mydriasis (77). The usual test for dependence is the appearance of withdrawal symptoms after removal of the agonist or after administration of an antagonist to precipitate withdrawal, with the antagonist being used more frequently. The withdrawal signs are similar for the two, suggesting that the resulting behavior is not an artifact of the method but is rather real withdrawal symptoms (535). Classic behavioral symptoms of naloxone-precipitated withdrawal include wet dog shakes (24,211), teeth chattering (211), muscle twitch (109), ataxia (24), a short-lasting increase in locomotion followed by a more prolonged decrease in it (535), jumping (24,270,338), lacrimation (192), altered urination ( 105,211 ), and diarrhea ( 109,192,211), accompanied by physiological changes, such as hyperalgesia (105,236), hyperthermia (105,192), tachypnea (192), and weight loss (105,192,211). There was no weight loss or decrease in intake of food, however, when the chronic morphine was given in food rather than through more traditional methods such as injection or infusion (535). There are also cardiovascular changes, with reports of hypertension in conscious rats (105) and people (192), but hypotension in anesthetized rats (109), as well as initial bradycardia followed by extrasystoles. More specialized responses have also been found to occur as a part of the withdrawal syndrome. Rhythmic fictive swallowing occurred after injection of naloxone in morphine-dependent rats, and the strength of the response was correlated with dose of morphine, so that the activity can be considered a good index of withdrawal (56). Hyperreactivity to vibration in crickets also occurred with removal of morphine after chronic injections, indicating dependence to the agonist had developed (579). There was a dramatic increase in evoked and spontaneous activity of the thalamic ventrobasal neurons after naloxone in morphinedependent rats, representing a neuronal correlate of withdrawal and hyperalgesia (248). Abstinence after chronic methadone produced symptoms similar to those with morphine dependence, including wet dog shakes, diarrhea, vocalization, and irritability (134). Methadone has a long-lasting agonist effect, since signs of dependence were seen for as long as 4 days after its single injection in experienced but not currently dependent users (491). Offspring of mothers maintained on methadone also showed withdrawal signs, such as mouthing and licking, hyperresponsivity to touch, vocalization, low body weight, and reduced survival rate (134). Preterm

1252 infants showed less severe abstinence symptoms than term infants, perhaps due to their shorter exposure to the drug or because of the immaturity of their opiate systems (124). Chronic administration of the opiate antagonist naltrexone also produced dependence, as indicated by supersensitivity to the effects of morphine, including both morphine-induced analgesia (319) and suppression of the rate of responding (576) after withdrawal of naltrexone. Apparently either chronic activation or blockade of the opiate receptors can lead to their altered responding. The relationship of a number of methodological variables to the development of tolerance was tested in 1991. One of those was route of administration of the morphine. Although there had previously been conflicting results about tolerance to IT administration, reports in 1991 indicated that this route produced tolerance (11,252,477,508), although the tolerance with IT and subcutaneous (SC) injection was weaker than that for ICV administration (508). Spinal injection of morphine also caused dependence, but some of its characteristics, especially withdrawal signs, were different from those from systemic morphine (105). Special populations, including different strains and species, were studied in the development of tolerance. Hamsters (451) and crickets (579) reacted in typical fashion, as did arthritic, as opposed to normal, rats (248), becoming tolerant with chronic presentation of morphine. There were, however, strain differences between obese and lean Zucker rats, with obese ones developing tolerance faster than the lean ones (172). Similarly, strains of mice reacted differentially to chronic morphine, with C57bl mice being unable to tolerate it, since all died within 12 hours of the implant, and CD1 mice being more sensitized to withdrawal than DDBA or C3H mice (361), indicating strong genetic differences among them. Even within a strain there were variations, based on supplier, on the sensitivity to morphine, although all developed equivalent degrees of tolerance after 72 hours of implantation of morphine (319). The degree of tolerance was a function of the total number of pellets of morphine implanted, not the relative amount on each day, since six pellets over 7 days produced greater tolerance than four pellets over 3 days (54). The magnitude of tolerance also was not related to the potency of the agonist, since 4 rag/ kg/h of morphine produced equal tolerance to 0.0085 mg/kg/h of sufentanil and to 0.45 mg/kg/h of alfentanil (262), or to the amount of morphine in the brain, since tolerance remained constant while analgesia decreased (263). These studies suggest that other physiological mechanisms might be activated by administration of chronic morphine. It is clear that dependence is a complex phenomenon influencing and being influenced by a wide range of physiological stimuli and systems. Application of the findings has not waited for complete understanding of the effects, so that clinical trials are occurring. The level of dependence in long-term heroin addicts can be assessed by the severity of naloxone-precipitated withdrawal on standard rating scales. Surprisingly, a substantial subgroup of addicts can use opiates regularly with low physical dependence, since their reactions to naloxone produced no clinically significant subjective or objective symptoms with this method (235). A more specific test to determine abuse relapse without relying on self-report or rating scales was adapted from studies of animals. Administration of naloxone produced a decreased startle response in dependent rats relative to drug-naive ones, suggesting a test that might be adapted to become an objective measure of an addict's returning to drug usage (332). It was also noted that sympathomimetics that are widely used in over-the-counter cold and cough medicines enhanced development and expression of tolerance when taken during the induction phase, but when taken

OLSON. OLSON AND KASTIN during the expression phase had no effect on tolerance and suppressed signs of withdrawal, with significant implications for addicts who use these products (110). Acute methadone detoxification can be induced by injection of naloxone during simultaneous sedation with midazolam, a fully reversible, short-acting benzodiazepine. Within hours, the patients were able to tolerate full doses of naltrexone, with minimal withdrawal symptoms, thus enabling them to transfer easily, quickly, and safely from methadone to naltrexone (310), which can be a difficult transition in many cases. The enkephalinase inhibitor acetorphan appeared to be a better agent to use than clonidine for treatment of withdrawal for patients addicted to heroin or synthetic opiates, since its effects were more marked on several objective signs and since the two were equal on subjective signs. In addition, no side effects were reported with acetorphan, suggesting its usefulness in therapy (192). Finally, although its usefulness is not clear, it was found that ingestion of amniotic fluid in morphine-dependent rats potentiated the action of an otherwise ineffective dose of morphine, producing analgesia and reversing hyperalgesia during morphine withdrawal. It was suggested that a placental opiate-enhancing factor might be useful in the treatment of addiction (125), although further delineation of the finding is obviously necessary before it can be applied to a clinical population. EATING

As in the past, the general finding in 1991 was that opiate agonists stimulated feeding and the antagonists suppressed it, although that was not always the case. As in other areas, receptor subtypes seem to be important here, and many variables that also modulate eating interact with the opiate system. There has been interest, as well, in the role that the opiate peptides might play in eating disorders and control of weight. An increase in eating was seen after administration of a number of opiate agonists, including morphine (181,182,567,569), DAMGO (28,298,567,568), DSLET (298), DPDPE (28,567,568), DALCE (20), ketocyclazocine ( 181,183), butorphanol (185), and U-50,488H (298,569). Some kappa agonists, however, were found in other studies to have no effect on eating, including U-50,488H (27,28) and ketocyclazocine (181), indicating weaker involvement of the kappa receptors. This seems especially true since two of the reports of facilitation of eating by kappa agonists also found that the effect was at least partially blocked by the mu antagonists naloxone (569), MR 2266, or naltrexone (183). Although injections of morphine, DAMGO, or DPDPE into the ventral tegmental area (VTA) of naive rats potentiated feeding (567), DAMGO did not do so when the rats had been given chronic amphetamine (27), indicating that the amphetamine blocked the effect. The nucleus accumbens is another structure that seems to be important in opiate, especially mu receptor, mediation of eating, since DAMGO markedly and DPDPE mildly facilitated feeding, but U-50,488H did not (28). Electrical stimulation of the anterior cingulate cortex stimulated eating, and the threshold for this was lowered by DAMGO but not by DPDPE (568), providing further support for the role of the mu receptors in eating. Similarly, the mu antagonist/3-funaltrexamine reduced feeding induced by D A M G O and DSLET (298), indicating mu involvement. A history of deprivation of food was necessary for the kappasigma agonist butorphanol to facilitate eating, since it prolonged food intake only in rats that had been repeatedly deprived during their development, suggesting that the early fasting possibly triggered changes in the opiate system that produce atypical feeding in adults (185). Even a single episode of deprivation lasting 18

OPIATES: 1991 hours can be important, since morphine and ketocyclazocine produced a generalized hyperphagic effect in free-fed animals but a biphasic one in fasted rats, with early hyperphagia being followed by later hypophagia (183). The effects of the peptides, however, were modulated by circadian rhythms and opiate dependence, reacting differently in the light or dark and after chronic or acute administration (181,182). Vasopressin and oxytocin attenuated the opiate hyperphagia in the light but not in the dark (181,182), suggesting a complex interaction of these variables affecting eating. Similarly, a known serotonergic anorexic, dexfenfluramine, reversed the stimulation of eating by DSLET, dynorphin, and/~-endorphin (383), indicating a serotonergic and opiate interaction in the modulation of eating. Use of the opiate antagonists provided further support for the role of the endogenous opiate system in the regulation of eating. As in previous years, they yielded highly consistent reductions of feeding, regardless of the antagonist used, including naloxone (43,88,142,174,199,220,261,299,354,448,568), naltrexone (42,48,183,241,261,274,464), /3-funaltrexamine (42,298), nor-binaltorphin (42,241), LY 255582 or its analogs (299,464), DALCE (a short-acting agonist but a long-acting antagonist) (20), naloxonazine (42), MR 2266 (183), and nalmefene (574). The inhibition by antagonists occurred under a wide variety of conditions, including deprivation-induced feeding (20,43,48,183,203,220,261,298), eating produced by stimulation of the lateral hypothalamus (88,568), stress-induced intake of food (199,353), high palatability-induced eating (220), and feeding resulting from injections of 2-deoxy-D-glucose (20), insulin (42), 8-OH-DPAT (142), opiate agonists (298), as well as freefeeding situations (174,241,274,464,574). There were some exceptions to the general rule, however, due to a number of different factors, including specific antagonists that were ineffective, such as naltrindole (568), or particular doses that had no effect even though other doses of the same agent were active (354). Interactions between antagonists and certain conditions also prevented the anorexic effects of the antagonists, since naltrexone was ineffective when rats were given chronic restraint stress (512) but reduced consumption in most other situations. Systemic administration of naloxone reduced feeding induced by the serotonin agonist 8-OH-DPAT injected SC or into the raphe nucleus, but when both compounds were microinjected into the raphe together, the suppressive effect of the naloxone was no longer evident (142), suggesting the effects of naloxone are mediated at a site distal to the raphe. That site might be the nucleus accumbens, since methylnaltrexone injected into it blocked the feeding responses to intra-raphe 8-OHDPAT (142). Although the kappa antagonist nor-binaltorphin decreased feeding transiently after injection of insulin (42), it had no effect on feeding induced by stimulation of the lateral hypothalamus (88) or on free feeding in either normal or polydipsic mice (241), supporting the notion of a weak role, at best, for kappa receptors in eating. The diet being consumed influenced the effect of the antagonists, since they produced differential consumption of macronutrients, although with conflicting results. Naltrexone caused extreme preferences in diet, with most animals obtaining more than 80% of their calories from carbohydrates and a few obtaining more than 90% of their calories from fats, but with the saline control, there were no such extremes (274). Naloxone reduced intake of a fat diet but not of a carbohydrate diet in fat-preferring rats, but in carbohydrate-preferring rats, the antagonist decreased intake of both diets equally (174). Naloxone also had a greater effect on intake with a high-fat diet than after deprivation of food, suggesting that palatability was important (220). In normal nondieting men, however, naltrexone affected only consumption of ice cream, increasing it, in a self-selection test (203). Hyper-

1253 phagia after exposure to a high-fat diet was potentiated by DALCE (20). Diet also altered the opiate system, since feeding rats fat or sucrose potentiated the analgesia of morphine or ethylketocyclazocine (EKC) (234). Clearly, more work needs to be done before any generalizations can be made about the mediation of macronutrients by the endogenous opiate system or vice versa. Aging and gender affected basal intake after deprivation, with a decrease in older and female animals, but the variables did not alter eating with a high-fat diet or sensitivity to naloxoneinduced hypophagia under either condition, with the exception that aging increased sensitivity for deprivation-induced eating (220), suggesting little role for either variable in opiate-mediated feeding. A variable that did alter the action of antagonists on eating was circadian rhythm, with receptor subtype being important, since the mu antagonist naltrexone had a greater effect during the dark phase and the delta antagonist MR 2266 produced a stronger anorexic effect during the light phase (183). Other systems, too, interact with naloxone-induced reductions in eating, with the serotonin antagonists methysergide, ketanserin, and ICS 205930 potentiating it but ritanserin having no effect or inhibiting it, depending on dose (43). The facilitation of eating by neuropeptide Y was altered by naloxone, suggesting opiate mediation of the peptide's effect on consumption (448). There was disagreement about whether the opiate antagonists alter eating by reducing the rewarding aspects of ingestion, especially taste. Studies using animal subjects found that the antagonists decreased palatability (220,250,261), but most of those using humans reported no effect (48,203). Both naloxone and naltrexone reduced feeding but not runway speed, indicating it was the reward value of food, not motivation, that was affected by the antagonists (26 l). Naloxone inhibited sucrose feeding to a level equal to that of nontreated rats drinking a less concentrated fluid (26 l) and was less effective in food-deprived rats than in normal ones (220,26 l), probably because the deprivation minimized the influence of taste. One study with humans also found modulation of eating by the antagonist nalmefene, with not only a decrease in caloric intake of a buffet style meal but also a decrease in ratings of pleasantness of the taste and smell of food (574). Other studies with human subjects, however, found little alteration of palatability, since ratings of food and hunger were unchanged after administration of naltrexone (48,203). Although naltrexone did not alter intake in one study (203), it did in the other (48), suggesting that the decreased consumption was due to less hunger, not less pleasantness. Although concentrations of plasma B-endorphin did not change after ingestion ofgiucose (29), after prolonged starvation (29), or after eating a French gastronomic banquet (348), administration of ~-endorphin delayed glucose disposal and decreased plasma insulin, especially in obese mice (256), suggesting only a smaU role for it in eating. Injection of U-50,488H and dynorphin increased both plasma insulin and glucose (257), and both Met- and Leu-enkephalin reduced blood glucose and inhibited release of the hyperglycemic hormone from the thoracic ganglia of shore crabs (Carcinus maenas) (318), further indicating a relationship between the opiate peptides and feeding responses. The concentration of B-endorphin in plasma is unrelated to age, height, or weight (191), and is unaffected by weight loss (584,585), suggesting that the peptide plays little role in the maintenance or reduction of weight. Opiate antagonists in some cases, however, have produced weight loss (105,273,299,354,407,464), indicating that the opiate system in general is probably involved in control of weight, even if 8endorphin is not. There were, however, some reports of the antagonists having no effect on weight (320,354,586), especially with a low dose (354). Chronic naltrexone did not block the

1254

OLSON, OLSON AND KASTIN

weight gain produced by consumption of sucrose, but it did induce a temporary increase in ingestion upon its withdrawal (320). Chronic morphine produced weight loss also (361,407), further suggesting a role for the opiates in weight control, although the nature of that role remains to be determined. Since there is some opiate modification of weight, it is logical to test whether the opiate system mediates eating disorders. Most work in this area has been done with obesity, indicating opiate involvement in it. Both plasma (434) and brain (255) concentrations of/3-endorphin are higher in genetically obese animals than in lean ones. The plasma disappearance kinetics for ~-endorphin are similar in lean and obese rats, indicating that the differences in concentration are due to production rather than turnover rate (434). The brain areas with the greatest increases in/3-endorphin, and also dynorphin, are in the hypothalamus, a structure well known to influence eating (255), lending support for the opiate role in obesity. Furthermore, obese rats were more sensitive to administration of morphine than lean rats (172), providing additional evidence for its involvement. Similarly, in humans the plasma concentrations of/3-endorphin were higher in obese than in normal individuals (29,168,426,584,585), even after weight loss (584,585), There was also a lack of normal circadian rhythm of/3-endorphin in obese people (29) and lack of a gender difference in obese individuals, although in normals the females have a lower concentration than males (426). The supply of/3-endorphin may be manipulated by the hypothalamic-pituitary-adrenal (HPA) axis, since its increased concentration in obesity was reduced to normal after dexamethasone (584), although contradictory findings of unresponsiveness of the peptide to the dexamethasone suppression test in obese subjects, even after weight loss, were reported (168). This finding suggests that the hyperendorphinemia in obese individuals may not be secondary to body weight excess (168). A carbohydrate meal reduced ¢/-endorphin in obese people, but a fat meal had no effect, indicating the macronutrients have an effect on release of the peptide (585). Manipulation of the opiate system has been used successfully in loss of weight in the obese, with naltrexone reducing the frequency of attacks of ravenous hunger (273) and decreasing the duration of binges in bulimics (18). Naioxone was more effective in increasing production of cortisol and luteinizing hormone in bulimic than in normal women, indicating increased opiate inhibition of the hormones in these patients (96). Further evidence of a role of an altered opiate system in bulimics and anorexics came from the report of elevated pain thresholds in those with eating disorders, relative to control levels. The disorders had different sources of opiate mediation, however, since the pain threshold was positively correlated with skin temperature in bulimics and negatively correlated with it in anorexics (290). Anorexics, like obese women, had a loss of circadian rhythm of ~endorphin, but also had a blunted response to clonidine and domperidine, suggesting an interaction of the opiate and aminergic systems in anorexia (68). There seems, therefore, to be evidence of opiate involvement in highly different eating disorders, with the possibility of manipulation of the opiate system producing effective therapy. DRINKING Interest in the possible role of the opiate system in drinking has decreased over the last several years, including 1991. The greatest amount of work in this area was devoted to a hypothesized link between the opiate peptides and consumption of alcohol, although, as in previous years, the results are inconsistent. More consistent findings were reported for the ability of opiate antagonists to inhibit intake of fluids, but the agonists produced

variable results. With drinking, as with eating, there was also interest in the modulation of taste preferences, presumably by the opiate reward mechanisms. Drinking was stimulated by administration of DAMGO (27) or thiorphan (149), and pretreatment with chronic amphetamine strongly potentiated the effect, suggesting an interaction between dopamine and the opiates. Mu receptors were probably involved since DAMGO worked but the kappa agonist U-50,488H produced no effect (27). Morphine tolerance inhibited intake of water temporarily, but lost its effectiveness by the end of 2 weeks (407). Previous morphine dependence did not alter daily consumption of fluids (213), but after morphine withdrawal, rats drank less overall, especially of a sweet solution (306). Thus, the actions of the opiate agonists are confusing and leave little opportunity for generalizing about them. A clearer understanding of the effects must await more systematic investigation of the issues, since most of the work in recent years has focused on other problems, such as taste preferences, assessing amount of intake only as a peripheral, control measure. As stated earlier, more consistent results have been reported from studies of the modulation of drinking by the opiate antagonists, primarily finding inhibition (41,149,241,250,267,464, 470,518). However, that general finding was altered by some specific variables, including age, since naloxone reduced drinking in mice up to a year, but had no effect in aged ones. The decrease in the effect of naloxone on intake in the old mice occurred only during the dark cycle and under conditions of water deprivation, suggesting that changes with age may be due to alteration of opiate mechanisms for the modulation of thirst (470). Genetic factors also play a role, since naltrexone suppressed drinking in inbred polydipsic mice but not in normal ones, unless a high dose was given ICV (241). The hypodipsia induced by inflammatory pain was not affected by naloxone, indicating that the effect was probably not opiate mediated (354). Although water intake was not altered by naltrexone, drinking of favored solutions was affected by the antagonist, indicating that taste is an important factor of opiate control (250). The relationship of the opiate peptides to taste preferences has, in fact, received more attention recently, since changing the preferences through modulation of the opiate system might reflect changes in opiate reward mechanisms. It appears that the opiate system influences palatability, because administration of agonists or antagonists appears to reduce preferences in most cases (250,261,306,518). Naloxone inhibited sucrose drinking to the level of nontreated animals drinking a less concentrated solution (261), and naltrexone reduced intake of preferred substances (saccharin and sodium chloride) but did not effect drinking of a less desired solution (quinine) or water (250). After morphine withdrawal, rats consumed less saccharin but not less water than controls, and in choice tests, the dependent rats had a reduced preference for saccharin, suggesting cross-tolerance between morphine and the opiate-mediated hedonic effects of sweet solutions (306). There were, however, paradoxical effects reported for morphine and naloxone, with each producing increased or decreased preferences for saccharin solutions, depending on specific doses of the opiate ligand and concentrations of the solution. The actions could result either from stimulation of opiate autoreceptors or from differential stimulation of different opiate receptor subtypes (518). Physiological support for opiate involvement in drinking came from a report that plasma concentrations of ~-endorphin increased after intake of a chocolate drink sweetened with either sucrose or aspartame, although the latter produced a larger rise. Insulin concentrations increased equally in both, suggesting that the increased ~-endorphin with aspartame was related to insulin secretion in the absence of marked change in glucose and the

OPIATES: 1991 direct liberation of~-endorphin by the sweetener (349). Plasma fl-endorphin also increased after administration of compound 48/80, a histamine liberator, and the rise was correlated with a facilitation of drinking of water. Naloxone blocked both effects and reduced angiotensin-induced intake of water, suggesting a possible involvement of the opiate system in the two forms of thirst (223). There was also an increase in the concentration of/~-endorphin in the testicular interstitial fluid after consumption of alcohol (7) and in the brains of rats exposed to alcohol prenatally (104), providing physiological evidence for the notion of opiate mediation of the drinking of alcohol. Moreover, repeated administration of ethanol increased the release of a-neoendorphin and decreased the release of Met-enkephalin-Argr-Gly7-Leus (MEAGL) from the rat hypothalamus in vitro, although a single injection of ethanol had no effect on either, indicating that chronic alcohol may alter the sensitivity of prodynorphin and proenkephalin neurons (41 l). Behavioral studies have also shown interactions between the opiate system and ethanol. Opiate antagonists suppress drinking of alcohol in some animals (149,221,267) but increase it in others, depending on selectively bred strains of rats (221), suggesting a genetic basis for ethanol preference. In monkeys with a prolonged history of alcohol drinking, naltrexone reduced intake of alcohol for the entire day, but in those that just had 2 days of alcohol abstinence, the antagonist reduced alcohol consumption only for a few hours. A lower dose of naltrexone was effective, but the net alcohol intake for 24 hours was greater than in those with continued availability of alcohol, suggesting abstinence altered the opiate system, producing greater ethanol-seeking behavior (267). The effect of opiate agonists on the drinking of alcohol, like their effect on intake of fluids in general, was inconsistent, dependent on the circumstances in which they were being studied. The enkephalinase inhibitor thiorphan (149) and morphine (369) promoted the drinking of alcohol in rats, and when the percentage of alcohol was changed, the rats altered the amount consumed to get the same amount of alcohol as before, supporting the hypothesis that an excess of opiate activation modulates the reinforcing features of ethanol (369). Furthermore, morphine increased ethanol intake when given half an hour before the test but decreased it if administered 4 hours before it, with the opposite results for naloxone. If the rats were given morphine then naioxone, the naloxone effect was potentiated, but if given morphine, then morphine again, the effect was attenuated. These results give additional evidence for the hypothesis that it is a surfeit, not deficit, in opiate activity that increases consumption of alcohol (422). In contrast, chronic morphine reduced preference for ethanol, and withdrawal increased the preference, suggesting that alcohol drinking is reinforced through an interaction with the endogenous opiate system and can compensate for deficiencies in opiate receptor activation (552). Whether opiate deficiency or surfeit is responsible for promoting alcohol consumption has not been established. In previously morphine-dependent rats, morphine increased preference for ethanol by itself or when given with a low (ineffective) dose of fluoxetine, a serotonergic reuptake inhibitor, which by itself reduced ethanol intake when given in an effective dose. Pimozide, a dopamine antagonist, and nalmefene, an opiate antagonist, also reduced ethanol consumption, indicating interaction of several neurotransmitter systems in the mediation of drinking of alcohol. These findings suggest that a long-lasting opiate antagonist may be an effective pharmacological adjunct to other treatments for alcohol abuse and alcoholism (213). Not only does the opiate system modulate intake of alcohol, but ethanol alters opiate-induced responses. Prenatal alcohol

1255 reduced isolation-induced analgesia and vocalization (251), indicating disturbance of stress responses after the early exposure to morphine, perhaps due to a permanent alteration of the opiate system. In alcoholics during withdrawal, morphine stimulated adenylcyclase activity, but in sober alcoholics, morphine inhibited it, and both effects were reversed by naloxone. Morphine's effect correlated with the severity of withdrawal and alcohol intoxication, suggesting that alcoholism may represent a disturbance of the endogenous opiate system (159). Morphine and buprenorphine increased ambulation in mice, with ethanol enhancing and naloxone inhibiting the effect, giving further support to the idea that the opiate system and ethanol interact (282). The exact nature of the interaction, however, is still unclear, since the results are frequently contradictory. GASTROINTESTINALAND RENAL FUNCTIONS As with the preceding area, interest in opiate modulation of gastrointestinal (GI) function has dwindled in recent years. In 1991, as in previous years, confirmation of the ability of the opiate agonists to slow GI transit was reported (31,82,277,294, 429,502,503), although not in all cases due to the specific variables used. There were strain differences among mice in their responsiveness to the agonists (31), and route of administration was important, since N-methylmorphine, a quaternary derivative that has little ability to cross the blood-brain barrier, was effective only if given ICV, indicating a centrally controlled mediation (82). The area of the colon studied was also critical, since U50,488H had no apparent effect on the cecum and ascending colon but delayed filling of the descending colon; DPDPE, however, was active at both sites (277). Not surprisingly, dose was another important variable, since morphine accelerated or slowed transit in the cecum and ascending colon depending on the dose used (277). Another possible determining variable is the species and/or kind of measure used, since the single study that reported an increase in transit by morphine used cats rather than rats and scintigraphic techniques rather than charcoal transit intervals (277). The particular agonist used also is influential, since most opiates inhibited transit, but dynorphin had no effect on it (469). There was some disagreement about the ability of naloxone to relieve the constipation induced by the use of morphine for pain in cancer patients. One study reported a reversal of the constipation without the return of pain, indicating withdrawal for the gut only, especially the colon, since small bowel transit time was not affected (502). Another study, however, found no effect of naloxone on morphine-induced constipation or GI activity, except in one patient, suggesting that the antagonist was not useful as a laxative (429). The difference might have been in the dose (503), since the former study used 20% of the morphine dose, but the highest dose in the latter study was only 10% of the morphine dose. The mu and delta, but not kappa, opiate agonists not only slowed transit in general, but they were able to block diarrhea induced by prostaglandin E2 in mice, and the inhibition was reversed by naioxone, indicating its opiate nature (294). The antagonist potentiated the inhibition of LiCl and cholecystokinin (CCK) on gastric motility but by itself had no effect, suggesting that the suppression was not opiate mediated (200). Inhibition of pyloric motility by a fat meal but not a standard meal, however, probably does have opiate involvement, since naloxone decreased the number of spike bursts at the gastroduodenal junction and the peripheral antagonist methyl levallorphan increased it when given IV but decreased it when administered ICV. Both antagonists given before CCK increased CCK's inhibition of the pyloric spike (313), leaving some question about the interaction of the opiate system and CCK.

1256 In vitro, as well as in vivo, the opiates produce a suppressive effect on the activity of GI tissues. Met-enkephalin, dynorphin, DPDPE, and Try-Pro-NMePhe-D-Pro-NH2, but not kappa agonists, reduced the amplitude of inhibitory junction potentials from circular muscle of baboon and human jejunum obtained from patients undergoing surgery. The effects of Met-enkephalin and dynorphin were blocked by the selective delta antagonist ICI 174,864, suggesting a role for the mu and delta receptors in this response (39). An analog of Leu-enkephalin, YGGFL, was rapidly metabolized when exposed to mucosa of rat jejunum, and the aminopeptidase inhibitor boroleucine or the enkephalinase inhibitor thiorphan slowed the YGGFL metabolism rate, with an additive effect for the two on YGGFL metabolism. The inhibition of metabolism did not enable YGGFL to permeate the membrane, but the addition of sodium glycocholate did allow the permeation. These findings demonstrate how barriers to transmucosal absorption can be evaluated and overcome and how the absorption varies with site (25). The endopeptidase EC 3.4.24. l I and aminopeptidases also contribute to the degradation of enkephalin by gastric muscle cells, since the inhibition of peptidases potentiates enkephalin-stimulated contractions of the cells (350). Support for this idea comes from the fact that EC 3.4.24.11 is found all along the GI tract, with high expression in mucosal layers (401). Specific binding sites in the pig small intestine were found for DAMGO. They tended to be localized in the basal portion of villous and crypt cells of the intestinal epithelium, suggesting that they may represent enkephalin receptors capable of modulating active electrolyte transport (415). In the GI tract of the snail (Helix aspersa), from the salivary glands to the posterior gut, cells were immunoreactive toward antibodies of Met-enkephalin,/~-endorphin, a-endorphin, and FMRFamide (334), indicating that the digestive functions might be regulated, at least in part, by the opiate system. FMRFamide-like immunoreactivity was also detected in the nervous system innervating the GI tract of the sea cucumber (161) and the crayfish (352), giving further support to the idea of opiate mediation of intestinal activity in a wide variety of species. There was also interest in the possible role of the opiate system in renal activity, but there were inconsistent results. The mu agonist dermorphin decreased sodium excretion and kidney flow without altering glomerular filtration rate or effective renal plasma flow. The changes of dermorphin were blocked by pretreatment with naloxone, indicating they were probably opiate effects, and by bilateral renal denervation, suggesting that mu agonists participate in the process of renal tubular sodium and water reabsorption by an intrarenal action that is dependent on an interaction with renal sympathetic neurons (237). Conversely, the kappa agonists bremazocine (55,103), ethylketazocine (103), U-50,488H (55,103), and tifluadom (103) produced a dose-related diuretic response. The effect of bremazocine occurred in the second hour, but not in the first, and that of U-50,488H was antidiuretic in the first hour but diuretic in the second hour (55). The timing might be the critical difference in the studies, since the one with dermorphin took measures during the first hour after administration. Furthermore, bremazocine has an antidiuretic effect after pretreatment with the a2-adrenoceptor antagonist idazoxan, so that renal regulation by the kappa agonists might be mediated by the ct2-adrenoceptors (55). Neither /-methadone nor naltrexone altered urine output (I03), and, although naloxone had no effect on renal function in normal individuals, the antagonist did increase urine output, creatinine clearance, and excretion of sodium and potassium in patients with cirrhosis and ascites. The diuretic effect of naloxone in the patients might be related to an increase in their glomerular filtration rate, possibly in conjunction with altered tubular reab-

OLSON, OLSON AND KASTIN sorption (293). In morphine-dependent rats, however, naloxone decreased urine output (105), presumably as a part of the withdrawal syndrome. Thus, there appears to be some evidence that renal activity is affected by the opiates and quite possibly is regulated in part by the endogenous opiate system. MENTAL ILLNESS AND MOOD

As with some of the preceding areas, interest in the possible modulation of mental illness by the opiate system has declined in recent years. Although early research suggested promise of new therapies for mental disturbances, these hopes have not been realized, so that attention has turned to other prospects. Some work in the area has continued, however, especially with regard to depression, which is a growing field of interest itself. Although there have been reports linking changes in the opiate system with changes in depression, they have been conflicting, and thus allow no definitive conclusions about what role the opiates might have in it. In rats bred for learned helplessness, an animal model of depression, plasma ~-endorphin concentrations were lower than in normal rats, and mu receptor densities were upregulated in all limbic regions, suggesting a role for the opiate system in depression (131). There was, however, no difference in basal ~endorphin in different types of depression (323), although there was greater suppression of the peptide in the dexamethasone test with minor depression and major depression without melancholia than in major depression with melancholia (323,324). Other measures, including concentrations of urinary free cortisol, plasma cortisol, and ACTH also were suppressed less in melancholia, indicating disturbed HPA axis activity in depressed patients (324). Further support for the involvement of B-endorphin in depression came from the report that concentrations of the peptide in cerebrospinal fluid (CSF) declined after electroconvulsive therapy, and the decrease was correlated with improvement in behavior (366), indicating that alterations of ~endorphin might be related to depression. Other studies found that higher, not lower, concentrations of ~/-endorphin were associated with less depression. In a subgroup of severely depressed cancer patients, physical activity raised both ~-endorphin and psychological well-being (583), and coronary patients with high depression scores had less of an increase of plasma ~-endorphin during exercise than those with low depression scores (307), indicating that depression may be related to a lower overall concentration of the peptide. There was, however, no correlation between CSF dynorphin and clinical measures of elderly depression in Alzheimer's patients (498), so that dynorphin is probably not involved in modulating the disorder. Behavioral studies have linked the opiate system to depression, since rats bred for learned helplessness were hyperalgesic in the tail-flick test and had fewer symptoms of naloxone-precipitated withdrawal (131). In another animal model of depression, forced swimming, the endogenous antiopiate MIF-l stimulated activity, thus relieving depression-induced immobility, further suggesting involvement of the opiate system in the pathophysiology of the disorder and indicating a possible clinical tool for its treatment (269). Addicts, who are dependent on opiate agonists, showed high scores on tests of major depression at the beginning of treatment with methadone (494,495), and the scores decreased with abstinence (495), providing additional support for the relationship between the opiates and depression. Patients with primary afl'ective disorders had different responses of growth hormone to naloxone or naloxone plus diazepam, indicating an interaction between the opiate and GABA systems in this disorder (546). There was, however, no difference between depressed

OPIATES: 1991 patients and normal individuals in response of cortisol and ACTH to opiate agonists and antagonists, indicating evidence against opiate involvement in a disturbed HPA axis in the patients (588). Thus, although there may be abnormal opiate activity in depressed patients, the nature of the relationship remains to be elucidated. Another disorder whose possible mediation by the opiate system has been investigated is schizophrenia. It was the first mental disturbance to be linked to the opiate peptides, but evidence since then has been disappointing. In 1991 it was reported that there was a higher concentration of immunoreactivity of the enkephalin analog MEAGL in schizophrenics than in normals, suggesting that a dysfunction of enkephalins might be present in the disease (217). There is a subgroup of schizophrenics that showed therapeutic responses to naloxone and another that responded to des-Tyr-7-endorphin (DT3,E), demonstrating opiate modulation of the disorder in at least some patients (365). Furthermore, the distribution of kappa receptors in schizophrenics differed from the pattern in controls. The fact that there was no consistent pattern within the schizophrenic population (438) may suggest a possible reason for the inconsistency in the field in general. Although it is highly speculative, there may be an endorphin mediation of the negative association between schizophrenia and rheumatoid arthritis, since in the arthritics there was a lowered concentration of fl-endorphin and in some schizophrenics there was an increased concentration of it (550). In some patients with self-injurious behavior, naloxone or naltrexone improved the symptoms (510,565), and facilitated learning and memory (510). Since plasma Met-enkephalin was higher in most patients with the disorder, it is possible that the opiates play a role in it, although evidence is weak and no definitive conclusion can be drawn (565). There was little support reported in 1991 for any role of opiate dysfunction in panic disorder, either, since neither fl-endorphin nor dynorphin(1-8) activity in CSF differed between normals and patients with it, although a negative correlation between phobia scores and flendorphin and a positive correlation between the peptide and anxiety ratings in normals were found (67). Anxiety scores did not correlate with plasma concentrations of fl-endorphin in another study (399). Conversely, increases in plasma fl-endorphin induced by suspension in a state of neutral buoyancy were accompanied by subjective reports of euphoria, relaxation, and well-being (520), and injection of morphine produced euphoria and drug liking, while the antagonist nalmefene induced agitation, irritation, and muscle tension (152). The conflicting reports make it difficult to determine whether there is any opiate mediation of these moods or of emotional disturbances in general, leaving involvement of the endogenous opiate system yet to be delineated. LEARNING, MEMORY, AND REWARD

There has been increasing interest in recent years in the possible mediation of learning and memory by the opiate system. Since there are many kinds of learning that respond differently to opiate modulation, it is difficult to make generaliTations about the effects of the opiates, although many studies find the agonists inhibit and the antagonists facilitate many kinds of learning. This enhancement by the antagonists and impairment by the agonists may involve an interaction with classical neurotransmitters, especially norepinephrine and acetylcholine, since the opiates inhibit their release in a number of brain regions. There is opiate peptide regulation of activities in cholinergic projections to the cortex and hippocampus, thus providing a potential mechanism for the opiate mediation of learning and memory (116).

1257 Many of the actions of the opiates are situation specific, increasing the difficulty of concluding anything definite about their role in these phenomena. Electroacupuncture, for example, produced analgesia that was potentiated by naltrexone on the first trial, but antagonized by it after two exposures, suggesting that an association of environmental cues with electroacupuncture by classical conditioning may be responsible for converting the analgesia from a nonopiate to opiate form (64). Similarly, pairing a distinctive environment with morphine developed an association between the two phenomena, since subsequent exposure to the environment produced morphine-like alterations in immune functions in rats (102). Additionally, in a discrimination paradigm in which injection of morphine was paired with shock and saline was paired with no shock, morphine produced conditioned suppression of drinking, indicating the agonist could be used as a conditioned stimulus in classical conditioning (6 l). Modification of discriminations in classical conditioning was also reported in 199 l, with the typical finding that opiate agonists can interfere with acquisition of the appropriate responses (202,345). Morphine reduced the eyeblinks to the conditioned stimulus associated with shock (CS+) and reduced differential responding between the CS+ and the C S - (not associated with shock), thus inhibiting the discrimination, possibly by attenuating the distinctiveness of the stimuli (343). [D-Ala2]Met-enkephaiinamide (DAMA) blocked and naloxone enhanced heart rate discriminations in rabbits during initial training trials, with the opiate effects being abolished by lesions in the sublenticular substantia innominata, although the lesions did not alter naloxone's ability to reduce habituation of the orienting response to a tone, indicating the specificity of opiate modulation of sublenticular pathways in learning (202). A low dose of the endogenous antiopiate MIF-l augmented the magnitude of the bradycardia to the CS+, but a larger dose of it deceased the amplitude, and both doses delayed extinction (201,202), providing evidence for involvement of the opiate system in learning. The acquisition of classically conditioned fear to the chamber in which the rats had been shocked was modulated differentially by opiate subtypes, since two mu antagonists, CTOP and naloxonazine, facilitated it, the kappa antagonist nor-binaltorphimine inhibited it, and two delta antagonists, 16-methylcyprenorphine and naltrindole, had no effect (136). The CS-induced suppression of the immune response was blocked by naltrexone, indicating that the learning does not directly affect the lymphocytes, but modulates the sympathetic output responsible for the alteration of the immune response (321). Conditioned suppression of licking, accomplished by pairing a tone and shock while the rat was drinking, was, however, not opiate mediated, since neither naloxone nor a stress that activates the opiate system typically affected its acquisition. It also might be the case that any opiate effects were state dependent, since testing was done in a different environment from that in which the shock was presented (398). The study did not differentiate between the alternatives, leaving the possibility of opiate involvement unclear. A specialized form of classical conditioning in which opiates have been tested is conditioned taste aversion. Here, a novel flavor is associated with a noxious event, so that when the flavor is presented again, it is not consumed. Both agonists and antagonists have been used as the unconditioned stimulus (US) that was paired with a novel saccharin solution. In morphine-dependent rats, the pairing of naloxone with saccharin resulted in an aversion to the sweet solution, as evidenced by subsequent avoidance of the saccharin (407), indicating that the naloxone was an aversive agent, probably producing withdrawal-like symptoms. Conversely, when morphine was paired with saccharin in morphine-experienced rats, it produced increased

1258 consumption of the saccharin, indicating taste preference and rewarding properties of the agonist (156). Similarly, the opiates have been used in conditioned place preference or aversion paradigms of classical conditioning, with the agonists typically producing place preference. The animal is usually injected with the agonist and then confined to a small chamber on some trials, and on other trials the vehicle is given and confinement to a different distinctive environment then occurs. When later given a choice between the two environments, the animal chooses the one paired with the agonist, indicating a preference for the cues associated with it. Conditioned place preference was shown after morphine (1,40,156,205,437, 467,499,500),a morphine metabolite (morphine-6-glucuronide) (1), DAME (13), DAMGO (499), DPDPE (499), methylenedioxymethamphetamine (MDMA) (57), and B-endorphin (480), and the effect was antagonized by naltrexone (1,57), indicating involvement of the opiate system. Chronic naloxone, however, potentiated morphine-induced place preference, perhaps due to an upregulation of opiate receptors in the CNS (500). Conditioned place aversions were produced by the kappa agonist U69593 (467) and naloxone (467,526), with a chronic lithiumcontaining diet abolishing the effect for naloxone but not for U-69593 (467). Since the diet had no effect of release of ~-endolphin in the brain, it was suggested that the action was not centrally controlled. In morphine-dependent rats, morphine produced place preference (156), and naloxone induced place aversion (204), so that the affective properties of the agents were altered by the chronic treatments. Site of administration was critical, since morphine injected intranigrally produced place preference but did not if given 1 mm caudal to this site, suggesting that the substantia nigra plays a role in morphine reward (40). Likewise, morphine into the VTA produced a place preference, but at other sites it did not (437). Not surprisingly, dose also was important, with only a low dose of morphine inducing the preference (437). For DAME infused into the medial preoptic area, however, there was no dose effect with the small (nanogram) doses studied, indicating an all-or-none effect in this situation (13). Other agents modified the place preference associated with the opiates, with pertussis toxin inhibiting it, suggesting G-proteins in the CNS may be involved in the motivating effects of opiate agonists (499). A selective CCKA antagonist also inhibited morphine's action, but a CCKB antagonist potentiated it, indicating differential modulation of the opiates by the subtypes of CCK (205). Serotonin antagonists blocked the place-aversion found after injection of naloxone in morphine-dependent rats, so that the antagonists may be useful clinically in opiate dependence involving conditioned drug effects (204). Place preference was also found for amphetamines, and naloxone blocked that learning, indicating that the reinforcement of amphetamine was mediated by opiate receptors (526). Similarly, substance P or an analog of it induced preference for an area associated with its administration, and naloxone pretreatment inhibited the effect at a dose at which the antagonist alone had no effect, suggesting that reward of substance P is opiate mediated (193). There are, therefore, a wide variety of agents that have appetitive or aversive properties involving opiate receptors that can be used as USs to condition acquired preferences or aversions for environments associated with them. Another form of learning that may be modulated by the opiate system is avoidance/escape training, although the findings here are contradictory. Infusion of DAMGO into the bilateral medial thalamus interfered with acquisition of an escape response, and since it also increased dopamine concentrations, the effect might be dopamine mediated. Neither U-50,488H nor DPDPE affected learning, however, suggesting that the action was a function of

OLSON, OLSON AND KASTIN the mu receptors, a conclusion that was supported by the finding that a selective mu antagonist, CTOP, but not the delta antagonist ICI 174,864 blocked the effect of DAMGO (89). A lower dose of the mu agonist, which did not alter escape training, inhibited conditioned active avoidance (89), as did the pretraining injection of DPDPE (342). Posttraining administration of DPDPE, however, facilitated the avoidance learning (342), suggesting a memory-enhancing effect for the peptide. Pretraining injection of morphine, though, had no effect on performance of an avoidance task (158); the response had already been acquired, however, so that the effect of the agonist was not measured on learning itself. To further confuse the issue, Leu-enkephalin or its metabolite Tyr-Gly-Gly given after training produced U-shaped dose-response curves, with intermediate levels interfering with shuttle avoidance and larger or smaller doses having no effect (458). This area, therefore, clearly lacks a systematic investigation of dose, time of administration, and receptor subtype, and no definitive conclusions can be drawn until such work is done. In a passive avoidance task, which is usually used to test memory instead of acquisition, there were also conflicting findings. Although antagonists consistently facilitated retention, whether given before training (559), after training (207,367), before testing (398), or chronically (510), the agonists produced variable results. Morphine administered before training inhibited retrieval (559), as did posttraining injection of Leu-enkephalin (564). Posttraining administration of~-endorphin also interfered with retention, but pretest injection of it facilitated memory (367), indicating opposite effects on consolidation and retrieval. In mice treated with scopolamine or cycloheximide, both of which inhibit retention, dynorphin(1-13) facilitated recall, and U-50,488H enhanced retrieval after cycloheximide, indicating antiamnesic effects for the two kappa agonists (530). Atropine methyl bromide or vagotomy abolished the inhibitory effect of Leu-enkephalin, suggesting cholinergic mediation of the action of the opiate (564). As with active avoidance, therefore, passive avoidance requires further systematic work before generalizations about the involvement of the opiate peptides in it can be clarified. Another task that tests primarily memory is the spatial learning paradigm, and not surprisingly, there were inconsistent results with it. Naloxone facilitated learning in the Morris water maze in meadow voles, but only in females, suggesting differential modulation of the task by the endogenous opiates in the sexes (157). Naloxone also attenuated impaired retention of spontaneous alternation in a Y-maze produced by scopolamine, as did glucose, supporting the hypothesis that release of cholinergic activity from opiate inhibition may contribute to glucose effects on behavior (554). The endogenous antiopiate MIF- 1, however, had no effect on learning of the Morris water maze or on inhibition of learning due to neonatal monosodium glutamate (573), indicating that the peptide did not act like an antagonist in this task. Morphine interfered with learning of both the Morris water maze (347) and spontaneous alternation in the Y-maze (493), being consistent with the general findings with mu agonists, but U-50,488H (377) facilitated memory, which agrees with the resuits with kappa ligands in passive avoidance. Administration of U-50,488H protected against ischemia-induced amnesia, and the effect was antagonized by the kappa antagonist MR-2266, indicating it was mediated by the kappa receptors. Conversely, however, poor retention in aged rats correlated with increased concentrations of dynorphin-like immunoreactivity in the hippocampus, suggesting that a dysfunction ofdynorphin regulation is related to cognitive impairment in the aged (587). The role of the opiate system in spatial learning, thus, remains to be delineated. In other tasks, too, the opiates seem to play a role. Although administration of MIF- 1 did not alter spatial learning, it or a

OPIATES: 1991 synthetic derivative of it, alalptide, facilitated memory of a rat to exposure to another rat, since the former spent less time in social investigation of the latter during reexposure to it but not to exposure to a novel rat (207). Chronic administration of naltrexone enhanced learning of a paired-associate task in a mildly retarded autistic patient (510), suggesting the possibility of an overactive opiate system in the disorder. The opiate peptides have frequently been used as discriminative stimuli (S°s), due to their subjective properties, so that when the opiate is presented, the organism learns to perform one task and performs another when the vehicle is presented. Typically, after training, generalization of the response to other opiates is tested to determine how similar their properties are to the original training stimulus. Morphine (209,371,406, 486,536,575,576), U-62,006 (209), EK-399 (a novel enkephalin analog) (371 ), EKC (371), N-allylnormetazocine (NANM) (371 ), buprenorphine (406), and naloxone (476) have been used successfully as S°s. Other substances that substituted for morphine include EK-399 (371), buprenorphine (575), etorphine (575), methadone (575), nalbuphine (575), and buprenorphine (575), and the reverse was true, with morphine substituting for buprenorphine (406). A substitute for U-62,006 was U-50,488H (209). Properties of EK-399 generalized partially to morphine and EKC, and EKC substituted partially for EK-399, but although NANM generalized to EK-399, the reverse was not true, suggesting EK-399 mainly involved mu action (371). Properties of naloxone generalized to diprenorphine, naltrexone, and nalorphine, all of which are mu ligands (476). Naloxone reversed the S° properties of morphine, indicating their opiate nature (486), and they were altered by subsequent development of tolerance to morphine, such that the dose to substitute for the original S° was increased (536). Although naltrindole, which may be a sigma ligand, alters dopamine function and dopamine function alters the effectiveness of cocaine, naltrindole does not influence the SD properties of cocaine, indicating that the presumed sigma receptors are not involved in them (72). The mu receptors, however, appear to be involved in modulation of behaviors mediated by the dopamine system, since both DA~ and DA~ agonists developed SD properties, and morphine substituted for the former, fentanyl generalized to both, and U-50, 488H did not substitute for either (229). The properties of the opiate peptides have been examined for their reward or aversive value, typically in terms of their modulation of responding for other reinforcers. One of those reinforcers is intracranial self-stimulation (i.e., working for electrical stimulation of pleasure centers of the brain). When injected into the rostral ventral pallidum, DAMGO suppressed self-stimulation, but increased it when injected into the caudal ventral pallidum (228), indicating that the site of injection is a critical factor, since nearby regions can produce opposite results. Similarly, the effects of naloxone varied as a function of the structure stimulated, antagonizing the reward function of VTA self-stimulation (198) and lateral hypothalamus stimulation (90) and the aversive property of stimulation in the mesencephalic central gray area (90). The antagonist also blocked the suppression of marijuana on ICSS, suggesting opiate mediation of it, probably through mu and delta receptors, since marijuana inhibited their binding (162). Responding for food is also modulated by the opiate peptides. Morphine suppresses the rate of responding in some cases (378,397,474,576), and naltrexone alone has no effect on the rate but antagonizes the effect of morphine (576). In rats that had been subjected to undernutrition in infancy, however, morphine had little effect on responding for food, with females being less sensitive than males (95), suggesting that the early deprivation of nutrition made food so rewarding that normal manipulations

1259 did not affect responding for it. In some situations, acute morphine or other agonists did not affect the rate of responding for food reward in rats (378), but chronic morphine (378,397) and fentanyl (397) shifted the dose-effect curve to the right. In rats (378) butorphanol also shifted the curve to the right, but in pigeons (397) and monkeys (378) it had no effect. Nalbuphine had no effect in rats or pigeons (378,397) but shifted the curve to the left in monkeys (378). Pentazocine and U-50,488H had no effect in rats or monkeys (378), and pentazocine slightly shifted the curve to the right in pigeons. Mu antagonists shifted the curve to the left in all three species (378,397). The bewildering effects, therefore, appear highly specific to species and agonist. The effects of the opiates on responding with a noxious stimulus are equally confusing. Morphine suppressed responding for time out from an avoidance schedule even though it did not alter avoidance conditioning, and morphine's effect was reversed by naltrexone, indicating opiate involvement (158). Naloxone alone had no effect on responding with a signalled punishment paradigm and did not influence the stimulation of responding by chlordiazepoxide, so that there was not an interaction between benzodiazepines and the opiate system (522). Self-administration of cocaine was inhibited by naltrexone (101,419) or naloxone (101), indicating that blockade of the opiate system attenuated the reinforcement properties of cocaine, but naltrexone had no effect on self-administration of nicotine (101), indicating that the endogenous opiate system probably does not play a role in the reward value of nicotine. Rats rapidly learn to self-administer dynorphin into the CA3 region of the hippocampus, an effect that is blocked by mu but not by kappa or delta antagonists (485). This region of the brain, thus, might be a target site for opiate reward and could be important in opiate dependence as a result. CARDIOVASCULAR RESPONSES

There has been increasing interest in the role that the opiate system might play in cardiovascular responses, and that trend continued in 1991. There were numerous studies looking at the modulation of heart rate and blood pressure by the opiate peptides, with mixed results, depending on a number of variables, especially route of administration. Although previous work had often focused on whether or not the subject was anesthetized, that did not seem to be a critical variable in the most recent studies, probably since most of them used anesthetized animals. Under most conditions, the agonists suppressed cardiovascular functioning, although there were many exceptions. Injection of Met-enkephalin directly into the nucleus ambiguus lowered heart rate (12), but an enkephalin analog, DAMGO, when administered into the preoptic nucleus at moderate doses, decreased heart rate, although a low dose increased it and a high dose produced a biphasic effect (47 I). A different enkephalin analog, DAME, however, did not alter heart rate when microinjected into the rostrat ventrolateral medulla (404). A still different analog, FK 33-824, administered ICV, had a biphasic effect, producing an initial tachycardia and then a sustained bradycardia. The bradycardia might be mediated in part by the cholinergic nervous system, since atropine potentiated it (416,417). Dynorphin(1-13) injected ICV decreased it (537), but when administered to either the second thoracic segment or IV, neither dynorphin( 1-13) nor dynorphin(1-17) affected the response (433). Intrathecal dynorphin(1-13) or dynorphin( 1-17) to the ninth thoracic segment stimulated heart rate, however, but neither opiate antagonists nor adrenalectomy affected it, indicating that the effect was nonopiate and through a sympathetic pathway that does not innervate the adrenals (433). Morphine given IV lowered heart rate, and although bilateral cervical vagotomy had

1260 no effect on it, preinjection peripherally of naloxone methobromide, which does not enter the CNS, blocked the suppression of heart rate by the morphine, indicating noncentral and nonvagal mediation of the response (420). Injection of/3-endorphin into the paraventricular hypothalamus produced an increase in heart rate that was blocked by naltrexone, indicating its opiate nature (227). Although intracisternal/3-endorphin had no effect on heart rate, the 1-27 fragment of the peptide reduced it (206). Administration ICV, however, of/3-endorphin reduced heart rate and its 1-27 fragment had a biphasic effect, with a transitory increase and then a longer decrease in it (537), indicating the importance of route of injection. Fragments less than 27 amino acids and N-terminally modified ones had no effect (537). Both a- and 3,-endorphin produced only a transient bradycardia, and their des-Tyr forms had no effect (537). Route of injection was also critical for the actions of morphiceptin, U-50,488H, and Tyr-D-Thr-Gly-Phe-Leu-Thr (DTLET) on heart rate in hypertensive and normal rats, with an IV injection of the latter stimulating it and of the other two decreasing it in all rats. With ICV administration, however, the opposite result occurred for morphiceptin and U-50,488H in hypertensive rats, but in normal ones ICV U-50,488H caused a lowering of heart rate. There was also a difference in subjects for the effect of ICV DTLET, with normotensive rats showing an increased heart rate and hypertensive ones having a decreased one (562). U-50,488H administered directly into the spinal cord had no effect on heart rate (433). There is, therefore, a confusing interaction between receptor subtype, route of administration, and cardiovascular status of rat in the modulation of heart rate by the opiates. The effects of the opiate peptides on blood pressure are equally muddled. Met-enkephalin decreased blood pressure when given IV, but when injected into the external iliac artery, it had no effect (80). Administration of Leu-enkephalin into the nucleus ambiguus also produced no change in blood pressure (12), but DAME lowered it when injected into the rostral ventrolateral medulla (404). Microinjection of D A M G O into the preoptic neuron increased blood pressure (471), but F K 33-824, given ICV, had a biphasic effect, first producing a transient hypertension, then a sustained hypotension. Atropine accentuated the hypotension, indicating cholinergic interaction with the opiates in the modulation of blood pressure as well as heart rate (416,417). Likewise, as with heart rate, blood pressure is modulated by DTLET, morphiceptin, and U-50,488H in a complex interaction with route of administration, receptor subtype, and whether the animal is hypertensive or not before the peptide is given. A delta ligand, DTLET, increased blood pressure when injected IV in all animals and ICV in normotensive ones, but reduced it in hypertensives. Both morphiceptin, the mu ligand, and U-50,488H, the kappa ligand, lowered blood pressure after IV administration in all animals, but after ICV administration increased it in hypertensives and lowered it in normals (562). U-50,488H IT had no effect on blood pressure at all (433). Similarly, the effects of/3-endorphin on blood pressure mirrored those on heart rate. If injected into the hypothalamus, the peptide increased blood pressure (227), but decreased it if injected ICY (537) or intracisternal (206). With ~-endorphin(1-27), however, both routes decreased blood pressure (206,537). Smaller fragments of ~-endorphin had no effect (206,537), a- and "rendorphin produced only a small transient bradycardia, and their des-Tyr forms had no effect (537). Dynorphin had varying effects, with ICY dynorphin(l-13) lowering blood pressure (537) and IV dynorphin(1-13) or dynorphin(l- 17) having no effect (433). As with heart rate, blood pressure was affected differentially by whether either dynorphin was given IT to the ninth or second

OLSON, OLSON AND KASTIN thoracic segment, with the former raising blood pressure and the latter not altering it (433). Morphine had a depressor effect that was independent ofvagotomy, indicating no vagal mediation in its action (420). The effects of the opiates on other cardiovascular measures were also somewhat consistent. Dynorphin produced vasoconstriction and thus reduced blood flow (311), as did Met-enkephalin (80) and DAME (404), but the action of DAMGO varied with dose, increasing blood flow at high doses and decreasing it at low doses (471). Administration of/3-endorphin or morphine reduced by 50% blood vessel proliferation in chick eggs, indicating that the peptides modulated angiogenesis (392) and, therefore, have an important effect on cardiovascular function. The results with injection of the opiate antagonists provided an equally confusing picture. Naloxone decreased heart rate in several different conditions, including with or without blockade of AVP receptors, indicating that AVP is not important in opiate action (445). It also lowered heart rate in morphine-dependent rats, followed by atrial and ventricular extrasystoles, actions that were abolished by clonidine but not atropine or yohimbine, indicating that the mechanisms were not likely to be cholinergic or noradrenergic (109). Although naloxone or naltrexone alone lowered heart rate, coadministration of them with ouabain or aconitine produced increased heart rate with a low dose of the antagonists and decreased it with a high dose of them. The ventricular extrasystoles elicited by infusion ofouabain or aconitine were not blocked by the antagonists, indicating no antiarrhythmic effects of them (238). In other studies, naloxone had no effect during feeding, but increased heart rate in nonfeeding situations (455), suggesting a possible interaction between the reward value of eating and cardiovascular functioning. Heart rate was also stimulated by CTOP, a somatostatin analog with mu antagonistic activity (459), and by FMRFamide (275), indicating that blockade of the opiate system by a variety of antagonists might influence heart rate. In other situations, however, naloxone had no effect on it (293,507), either in controls or in patients with cirrhosis (293). Similarly, the antagonists have varying effects on blood pressure, depending on the specifics of the conditions under which they are studied. Naloxone increased blood pressure in morphine-dependent rats that were conscious (105) but lowered it in anesthetized rats (109). It also raised blood pressure during exercise (138), and reversed the hypotension induced by propranolol (507) but attenuated the hypertension produced by deoxycorticosterone (586). Other antagonists, including ICI 154,129 (272) and MR 2266 and MR 1452 (271), lowered it. Naloxone was found in other studies, however, to have no effect (I 38,293,507), thus leaving the field a set of conflicting results. Opiates also may be involved in some types of hypertension. In individuals with mild to moderate essential hypertension, there was a correlation between clonidine-lowered blood pressure and raised plasma/3-endorphin, but there was no correlation between increased/3-endorphin and lowered blood pressure after the dopaminergic D2 agonist bromocryptine, stressing the importance of central sympathetic activity and not only direct pituitary dopaminergic agonist activity in this situation (17). Support for the modulation by the opiate system of sympathomedullary discharge came from the fact that naloxone increased epinephrine and cortisol, 13-endorphin, and blood pressure in the cold pressor test, although the responses were similar for normotensives and hypertensives (215). Since naloxone attenuated the development of hypertension in rats given deoxycorticosterone acetate and fed a high-salt diet, it was suggested that central opiate receptors play an important role in the pathogenesis of this model of hypertension (586).

OPIATES: 1991 The opiate systems of spontaneously hypertensive rats (SHR) have been studied to discover whether they differ from those of normotensive rats to determine whether the opiates mediate this genetic form of hypertension. The SHRs had lower cardiac concentrations of Met-enkephalin and increased amounts of preproenkephalin mRNA, and displayed a greater circadian rhythm for the variables relative to normotensives (130), indicating a disturbed opiate system in SHRs. The SHRs also had lower binding densities of mu receptors in CA 1 of the hippocampus but higher binding densities of mu and delta receptors in other areas (281), providing more evidence for a role of the opiates in high blood pressure in these rats. Additionally, administration of ~-endorphin into the paraventricular hypothalamus raised blood pressure more in SHR than in normal rats (227). Furthermore, the kappa antagonists MR 2266 and MR 1452 delayed the age-dependent increase in blood pressure in SHRs but not in normals (271 ), suggesting the importance of the kappa receptors in this disorder. Naloxone potentiated the vasodilator response produced by transmural nerve stimulation, but ICI 174,864 had no effect, and CTOP inhibited the response in a naloxone-reversible fashion, indicating mu opiate receptors were probably involved (303). Naloxone also increased hindquarter blood flow resistance during rapid hypotensive hemorrhage, but blockade of vasopressin receptors did not alter it, suggesting that vasopressin did not play a role in the opiate action of this responses (445). Thus, the endogenous opiates appear to mediated blood flow in at least some situations. The opiate system might also be involved in the pathophysiology of experimental shock, especially in hypovolemia, although the nature of its role in not well understood. After hemorrhage, concentrations of Met- and Leu-enkephalin, dynorphin, and ~-endorphin increased in CSF. When applied topically to the cortical surface,/3-endorphin decreased artery diameter, but the other three increased it, and hypotension attenuated the dilation but had no effect on the constriction, suggesting that the endogenous opiates could contribute to cerebral circulation during hypotension (21). Although naloxone alone had no effect on cerebral blood flow or vascular resistance of normotensive or hypotensive animals during hemorrhage, it did inhibit the suppressed circulation induced by indomethacin during hypotension, indicating a partial mechanism of the opiate effect (22). Naloxone also raised blood pressure in hypovolemia (445,446) and protected against hypotension during bleeding in normal but not in adrenalectomized rats, suggesting an opiate mechanism interacting with adrenal corticosteroids in the regulation of hemodynamics during hemorrhage (132). Other forms of shock also may be opiate mediated in part. Injection of anti-B-endorphin serum after burn shock increased survival time and delayed the decrease of blood pressure and heart rate, and the onset of abnormal changes in electrical activity of the heart (210), indicating that/3-endorphin may have a deleterious effect in this situation. Production of ~-endorphin also contributes to the pathophysiology of endotoxic shock, probably through a complex mechanism with the immune system (190). Other cardiovascular disorders are also associated with changes in the peptide, since plasma ~-endorphin increased in congestive heart failure, and the changes were correlated with cardiac performance (246). Another cardiovascular response involving the opiate system is ischemia, although it, too, had conflicting outcomes. The administration of dynorphin after three-vessel occlusion increased survival rate and resulted in less infarcted tissue and edema in the brain (561). The kappa agonist PD 117302 also conferred neuroprotection, inducing faster recovery after occlusion (164), as did U-50,488H and three of its isomers (98), and the novel,

1261 highly potent and selective kappa agonist GR 89696 protected against neural damage in two different animal models of cerebral ischemia (58), suggesting the importance of the kappa receptors in this response. Application ofdynorphin directly to the cortex, however, produced vasoconstriction, reduction of blood flow, and cortical lesions, indicating that the peptide could be used as a new method to induce ischemia and injury (311) as well as to protect against the injury. Concentrations of opiate peptides increased in the brain after cerebral ischemia, and neuronal damage occurred if occlusion was greater than 30 minutes, suggesting that sustained elevation of the opiates is needed for damage (484). Further support for that idea comes from the finding that antagonists can lessen damage, since naltrexone reduced pain and improved circulation after ischemia (189), and naloxone or nalmefene protected against ischemia, perhaps by inhibition of endogenous opiates (312). Naloxone also improved oxygen supply and electrical activity of neurons in ischemia (121). Plasma /3-endorphin increased in coronary patients who experienced ischemic pain during exercise (307), indicating that the agonist was correlated with cardiac difficulties. It is not clear, however, under what conditions the opiates cause damage or protect against it. The effect of opiates on cardiovascular functioning in vitro was also investigated in 1991. Morphine, levorphanol, dextrophan, and naloxone all potentiated the stimulatory effects of the fl-adrenergic agonist isoproterenol on isometric tension in the isolated rabbit right ventricular myocardium. This might have occurred by a novel mechanism unrelated to binding of these drugs to opiate receptors, since it was not agonist specific or stereospecific and only occurred at some doses. It might have increased sensitivity to stimulation by circulating catecholamines and might explain the paradoxical augmentation of myocardial contractility by either class of agents under a variety of experimental and clinical conditions (257). The endogenous antagonist FMRFamide increased heart rate (179,352) and increased the amplitude of cardiac contractions in the isolated heart (352), suggesting that FMRFamide might play a role in the regulation of heartbeat. The antagonist activated calcium channels and initiated sodium and barium currents in the isolated heart (70), indicating a possible mechanism for its effect. There are, therefore, a variety of cardiovascular responses that are modified, if not regulated, by the opiate system, but the exact nature of their actions remains to be determined. RESPIRATIONAND THERMOREGULAT1ON As in recent years, in 1991 there was less attention paid to the possible role of the endogenous opiates in respiration and thermoregulation than in the early years of opiate research. The well-known clinical finding that the opiate agonists depress respiration was supported by findings that morphine (496), dermorphin (472,553), and the enkephalin analog FK 33,824 (416,417) reduced it in the laboratory. Injection of FK 33,824 both ICV and into the nucleus tractus solitarius depressed respiration and was fatal at higher doses (416,417). The inhibition of breathing by dermorphin was reversed by the a2-adrenergic antagonist SK&F 86466, indicating an interaction between the opiate and SK&F 86466 at the mu2, not mul, receptor, since analgesia was not affected (472,553). The mut receptor does not reduce respiration (412), so that SK&F 86466 may have clinical potential as an analgesic. Similarly, the mixed kappa, and kappa2 ligand nalbuphine produces analgesia with little respiratory depression (396). Mu, but not kappa or delta, receptors mediated the depression of respiration by morphine, since it was antagonized by/~-funaltrexamine but not by nor-binaltorphimine or naltrindole (496). The kappa agonist U-50,488H, however, en-

1262 hanced energy expenditure, since it increased oxygen consumption in both resting and free-moving rats, although at a lower dose in resting ones. The effect was independent of the agonist's action on activity and was suppressed by the kappa antagonist MR 2266, so that it was probably mediated by kappa receptors (330). The opiate system might also play a role in maturation of the respiratory system, since/3-endorphin decreased ornithine decarboxylase activity in the lungs of preweanling rats, but the peptide's effect was probably indirect, through mediation ofglucocorticoids, since ~-endorphin increases plasma corticosterone (178). Immaturity in respiration as measured by apneic bouts, however, was not correlated with plasma/3-endorphin in infants physically stressed perinatally (297). In fetal lambs, the endogenous opiate system may play a tonic role at the mu~ receptor to maintain both stability and continuity of fetal breathing movement patterns, since morphine reduced the number and duration of apneas and increased the number of diaphragmatic bursts in the lambs. The effect was abolished by pretreatment with naloxonazine or concurrent administration with ICV methylnaloxone (505). In addition, naloxonazine, a highly specific, irreversible mu~ antagonist, but not naloxone, a less selective antagonist, reduced regularity of breathing and produced fragmented patterns of breathing in the lambs (91). Naloxone also had no effect on the response to hypoxia of fetal lambs (301). Postnatally, too, the effect of the endogenous opiates on ventilation during stress is often studied by administration of opiate antagonists. After cerebral ischemia, naloxone improved oxygen supply ( 121), thereby facilitating recovery from the hypoxia induced by the ischemia. Naloxone also increased minute ventilation in hypercapnic cats (523) and stimulated breathing in chronic or acute hypoxia (400), suggesting modulation of the effects by the opiate system. Naltrexone increased flow-resistive loading in anesthetized piglets during hyperoxic CO2 rebreathing, indicating a facilitating effect of the antagonist (460). In patients with obstructive sleep apnea syndrome, naloxone shortened the duration of apnea, increased the tidal volume of the first postapnea breath, and increased the interapnea period, providing evidence that the endogenous opiates might mediate the effects of this disorder (176). The enkephalinase inhibitor thiorphan, furthermore, potentiated the inhibitory effect of neurokinin A in asthma, thus exacerbating it, providing further evidence for a suppressive effect of the opiate system in respiration (150). The endogenous opiates had less consistent actions on thermoregulation. Morphine was reported to increase body temperature in some situations (2,53,54,95,243,347) but reduce it in others (54,243). Part of the difficulty may result from the finding that dependence results in hypothermia, but tolerance produces hyperthermia (54). Another possible explanation for the differences may be that the effects of morphine depend on the preinjection temperature and the part of the day-night rhythm of temperature during which the measure is made. In quails with low temperatures, during the day there is a multiphasic action, with an increase, then a decrease, and then a weak increase after morphine, but in those with higher temperatures, there is only the decrease followed by a subsequent increase. At night all birds have a biphasic reaction to morphine, first increasing and then lowering their temperature. Naloxone blocked the effects of morphine and by itself reduced the day temperature in birds with higher temperatures and had no effect at night, suggesting that the endogenous opiate system is involved in thermoregulation, at least in the quail (243). Administration of other agonists had different effects. Body temperature decreased after U-50,488H (10,5 l), but there was no difference between those tolerant to the peptide and controls (51). At low doses the kappa agonist potentiated the reduction

OLSON, OLSON AND KAST1N of body temperature by chlorpromazine, and at high doses it produced an additive effect, indicating an interaction between the two drugs (10). Dynorphin, however, had no effect on body temperature in mice (469). In general, the opiate antagonists had no effect on temperature (84,243,347,354,573). Since naltrexone was tested in rat pups at 7 days of age, it is possible that thermoregulation by the endogenous opiates had not yet developed and that it might occur only in older animals (84). Naloxone did not alter the increased core temperature produced by inoculation of the rat paw by Mycobacterium butyrieurn, indicating that the effect was probably not mediated by the opiate system (354). Although MIF-1 did not change colonic temperature, the endogenous antiopiate did potentiate d-amphetamine-induced hypothermia, suggesting that there might be an interaction between the two drugs (573). Naloxone, however, lowered body temperature in postmenopausal women, with estradiol potentiating the effect of the antagonist. Progesterone plus estradiol produced hyperthermia, an action not affected by naloxone, and inhibited the ability of naloxone to lower temperature, suggesting mediation by the opiate system of the thermal effects of estradiol but not progesterone (81). Naloxone induced hypothermia in the daytime but had no effect at night (243), providing further support for the cyclical variations in the modulation of temperature by the endogenous opiates. Naloxone-produced withdrawal in morphinedependent animals reduced body temperature (95,362), but hyperthermia resulted in those rats made dependent by spinal administration of morphine (105), supporting previous findings of differences in the characteristics of dependence between systemic and spinal injection. Overall, therefore, the evidence for mediation of thermoregulation is unclear. SEIZURES AND OTHER NEUROLOGICALDISORDERS In 1991 there was continued interest in the possible opiate mediation of seizure activity and other disorders, although the level of activity in this area was not as great as in the early years of opiate research. In general, it was found that the opiate agonists tended to stimulate or facilitate seizures and the antagonists seemed to protect against them, although there were also reports of no opiate activity related to them. Both DAMGO and DPDPE produced naloxone-reversible epileptiform bursting in the CA l rat hippocampus, with DAMGO being more potent. Morphine and the mixed mu and delta agonist DAMEA also induced it, but the effect was only partially antagonized by naloxone and was not affected by the delta antagonist ICI 154,129. The enkephalinase inhibitors thiorphan and SCH 32615 had no seizure activity but potentiated the effects of DAMGO and DAMEA, suggesting a role for the endogenous opiates as proconvulsants (115). Likewise, the kappa agonists PD 117302, U-50,488H, and U60593 induced convulsions, but a non-kappa opiate (+) enantiomer of U-50,488H, and U-53445E, did not (32), suggesting that the convulsions produced by the kappa agonists involve a stereospecific opiate receptor mechanism. Dermorphin, a mu agonist (167), and pentazocine, a sigma ligand (123), also stimulated seizures, but the delta agonist dermenkephalin did not (167). The effect of pentazocine was facilitated by naloxone, since a combination of noneffective doses of pentazocine and noneffective doses of naloxone produced seizures (123). Electrical seizures induced by dermorphin, however, were reversed by naloxone (167). Although proenkephalin mRNA did not change in the striatum, frontal cortex, or hippocampus after kindling, it did increase in the olfactory tubercle and arcuate nucleus (465), providing another line of evidence to support the notion that the opiate system can facilitate seizure activity. Convulsions

OPIATES: 1991 produced by maximal electroshock, however, were unaffected by PD117302 (112), and U-50,488H and U-54,494A were ineffective in depressing epileptiform bursting in CA1 slices (408), indicating that some kinds of seizure activity are probably not mediated by the opiate system. Naloxone inhibited convulsions kindled by electroconvulsive shock (224,231) and reversed unconsciousness after seizures (528). It also increased benzodiazepine binding in the substantia nigra, an effect that persisted during kindling, possibly contributing to the seizure-suppressive effect of naloxone (431). Cyprodine, another mu antagonist, also attenuated seizure activity (224). Naloxone did not block the latency of the electroconvulsive shock-induced seizures in mice subjected to cold-restraint stress or swim stress; however, it did delay the onset of pentylenetetrazol-induced seizures in these stressed mice, suggesting a complex relationship between the opiate system, stress, and convulsions (ll7). Nor-binaltorphimine did not affect the threshold for electroshock seizures, but naltrindole lowered it, indicating that the delta ligand was a proconvulsant agent but the kappa one was not and suggesting that the anticonvulsant action is mu mediated (224). For hyperthermia-induced convulsions, however, the kappa antagonist MR 2266 and the delta antagonist ICI 154,129 blocked seizures, and the mu antagonist fl-funaltrexamine did not (288), suggesting differential receptor subtype involvement for different types of seizures. Chronic administration of naloxone modified the acquisition of seizure activity in amygdala-kindled rats, facilitating states IV and V in some, producing variability of electrical and behavioral responses to kindling in others, and enhancing postictal seizure suppression in all rats (430), indicating opiate modulation of the seizures in a complex way. To further complicate matters, naloxone injected into the diagonal band of Broca or the medial preoptic area produced seizures. The mechanism was unclear, but it was suggested that naloxone might have activated cholinergic neurons in those areas, probably through GABA blockade, which produced a disinhibition of the neurons (194). Seizure activity has been shown by positron emission tomography to change the opiate system, with increased mu binding in the temporal lobe ( 151,344), but not in the hippocampus ipsilateral to the seizure focus (151). In one study there was a slight but not statistically significant increase in mu binding in the amygdala (151), but in another there was a decrease (344), so that no definitive conclusions can be drawn. Stimulation of the perforant path produced convulsions and an accompanying decrease in Met-enkephalin and dynorphin(1-8) in the hippocampus, suggesting that the endogenous opiates may play a role in limbic system epileptogenic phenomena (356). Electroconvulsive therapy increased plasma/3-endorphin in some patients and decreased it in others, with no known variables offering an explanation for the differences (577). In genetically epileptic mice, concentrations of Met-enkephalin were higher than in normals in the cortex, striatum, pons, and enkephalinergic pathways (393), suggesting a possible mechanism for their disability. It remains, however, to be determined what role the opiate system has in the pathogenesis of epileptic activity. It has also been thought that the endogenous opiates may be involved in reactions to injury to the spinal cord, since there was a large and rapid upregulation of preprodynorphin mRNA after chronic constriction injury or peripheral inflammation of the sciatic nerve but not with transection or crushing of that nerve. This indicates that opiate gene expression is affected only by certain types of injury (128). Injection of U-50,488H before and after contusive spinal cord injury decreased vascular permeability, the vascular injury index, and edema formation, so that it had a protective and beneficial effect on damage in this model of CNS trauma (414). Administration of the kappa ligands

1263 U-50,488H or nalmefene, or a TRH analog with no kappa binding, YM-14673, increased open field walking after spinal injury by a displacement-controlled impact device, and the YM- 14673 also improved grid walking and incline plane scores, arguing against a kappa-mediated mechanism of injury (44), but still implicating the opiate system. Naloxone, however, had no effect on neurologic function after compression-induced spinal cord injury (195), and administration of dynorphin( l - 13) IT resulted in permanent loss of the tail-flick reflex and temporary hindlimb paralysis, with tolerance developing to chronic dynorphin (487), thus confusing the picture and questioning the role of the opiate system here. The endogenous opiates might mediate functioning after brain injury. After injection ofNMDA intracerebrally to produce brain injury, the kappa agonist U-54,494A produced protection against dysfunction, and when given both before and after the injury, it and U-50,488H offered neuroprotection (214). Norbinaltrexamine, however, also improved neurologic outcome when given 2 weeks after fluid percussion brain injury. The rats had greater intracellular free magnesium and cytosolic phosphorylation potentials, and the cytosolic phosphorylation potentials were correlated with neurological function, supporting the hypotheses that kappa receptors mediate pathophysiological changes after brain injury and that the benefits of the antagonist come from increased cellular bioenergetics (549). Naloxone, furthermore, increased the mitotic index of prenatally X-irradiated brains of rats during a 24-week postnatal observation period, especially the transient hyperplasia of the subependydmal layer at 4-6 weeks, revealing that the repair was under a strong suppressive effect of the opiate system (449). Increasing interest has developed in the possible role of the endogenous opiates in the etiology of Parkinson's disease. There appears to be a decrease in Met-enkephalin in the caudate of postmortem parkinsonian brains, but only if there was at least an 80% loss ofdopamine, suggesting the loss of Met-enkephalin might be secondary to that of dopamine. The decrease in the opiate peptide might contribute to the loss of memory and movement in the patients (473). No change in dynorphin was found in the caudate, nor was there a loss of either opiate peptide in the frontal cortex (473). Similarly, there was a failure of a proenkephalin derivative, MERGL, to increase normally with age in the CSF of Parkinson's patients, but the concentration of dynorphin(1-8) was unaffected, supporting the idea that the abnormality of the enkephalin system in the disease might be due to involvement of striatal neurons in the primary pathologic process (34). Adrenal medullary tissue also had lower concentrations of Met-enkephalin in these patients (492), further supporting a role for the peptide in the disease. In contrast, monkeys made hemiparkinsonian by unilateral administration of the neurotoxin MPTP had a higher density of opiate receptors in the caudate and putamen in the treated side, and in the striatum the treated side had more extensive patchy distribution of binding sites, a finding previously shown with unilateral dopamine denervation by 6-OHDA (403). Similarly, in the monkeys, the severity of their symptoms correlated with a large number of intensely enkephalin-immunoreactive perikarya in the putamen, contrasting to no such perikarya in normals (107). The differences between the human patients and the animal model were not explained, although it could be that decreased concentrations of the peptide might led to increases in opiate receptor density, an adaptation like that of supersensitivity of dopamine receptors after dopaminergic denervation by 6-OHDA (107). Naloxone increased the concentrations of ACTH and cortisol in the blood of Parkinson's patients to a greater degree than in normals, showing decreased opiate inhibitory control of their

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OLSON, OLSON AND KASTIN

secretion and agreeing with the findings of opiate deficiency in the patients (551). Naloxone also attenuated the overstimulatory effects of L-DOPA in rats given 6-OHDA to deplete dopamine unilaterally. The lesions that resulted produced spontaneous ipsilateral rotation. Treatment with L-DOPA reversed the direction of the rotation, and naloxone decreased the L-DOPA-induced contralateral rotations and increased the ipsilateral ones, indicating an interaction between opiate and dopamine pharmacology in the disorder that might be of theoretical and clinical significance for parkinsonism (85). The relationship of the endogenous opiates to other disorders was also reported in isolated studies in 1991, including Alzheimer's disease. Alzheimer's patients had a 40% decrease in CSF dynorphin(l-8), relative to age-matched controls, but the concentration of dynorphin did not correlate with clinical variables (498). The concentration of/3-endorphin in the cerebral cortex of Alzheimer's patients was also lowered, but it was normal in the CSF (127), so that its role in the disorder is not clear. In postmortem brain tissue from Huntington's patients there was a decrease in the density of striatal neurons with preproenkephalin mRNA, but only if the patient was symptomatic. In presymptomatic patients, there was less enkephalin immunoreactivity in the external globus pallidus, so that an early loss here is not related to the generalized death of striatal enkephalinergic neurons early in the course of the disease (16). In a patient with Tourette's syndrome, treatment with the opiate oxycodone for pain also resulted in a decrease in symptoms. Efforts to stop treatment later caused a marked exacerbation of the self-harming tics, and a brief reinstitution of the treatment produced a dramatic improvement, suggesting that the opiate system might play a role in the disorder (74). Patients with Rett syndrome had raised concentrations of 13-endorphin in the CSF, but the severity of symptoms was not correlated with it, so that it is unlikely to be of primary pathologic significance (370). There were indications of opiate dysfunction in some types of headache, since concentrations of/3-endorphin in peripheral mononuclear cells was lower than normal in patients with cluster and migraine headaches, but not with episodic tension headache, with the decrease for cluster headaches greater than for migraine (442). The expression of dopamine-induced oral stereotypy, which is the animal model for tardive dyskinesia, was inhibited by administration of naloxone, suggesting that it might be possible to prevent the development of tardive dyskinesia associated with use of neuroleptics by treatment with naloxone (402). Thus, the endogenous opiates have been tentatively linked to a number of disorders, but the opiate role in their pathogenesis remains to be discovered. ELECTRICAL-RELATEDACTIVITY Interest in the study of the effects of the opiate agonists and antagonists on neural activity increased in 1991, although it had been high for several years. Among the concerns are the actions of the opiates on brain activity measured by cortical electroencephalographic (EEG) techniques, by potentials specifically in the hippocampus or spinal cord, and by functions in other areas of the nervous system. Interactions with other systems, especially the dopamine system, also received attention, as did opiate mediation of sleep. An enkephalin analog increased the spectral power of several EEG bands, especially bands 1 and 2, as did morphine. These effects were blocked by naltrexone, which crosses the bloodbrain barrier, but not by methylnaltrexone, which does not cross the blood-brain barrier, or by MIF-1. This demonstrated that a peptide could cross the blood-brain barrier in amounts sufficient to induce a direct biologic effect (239). Morphine also pro-

duced antagonist-reversible EEG desynchronization (100,504) and an activation of fetal EEG patterns, including a decrease in high voltage slow activity and an increase in low voltage fast activity (504). Dermorphin, likewise, induced EEG spiking that was attenuated by naloxone (167). Iontophoretically applied dynorphin or Leu-enkephalin to the hippocampus of intact animals produced predominately excitatory responses that were unaffected by castration or ovariectomy, although gonadectomy did alter the basal firing rate, indicating no interaction between the sex steroids and the opiates on these responses (384). Dynorphin(l-8) and Met-enkephalin did attenuate responses to stimulation of the perforant path, the major input to the hippocampal formation, but the effect was not blocked by mu or delta antagonists (356), questioning whether this was an opiate response. In hippocampal slices, Metenkephalin, Leu-enkephalin, and the enkephalin analogs, DPDPE, DSLET, DTLET, and DAMGO, increased the amplitude of evoked primary population spikes, but an analog of deltorphin with delta receptor affinity had no effect, suggesting that subtypes of the delta receptors had differential actions (556). Morphine increased population spikes in hippocampal slices (283), as did DAMGO and DPDPE for extracellularly recorded feedforward and feedback inhibition in the hippocampal slice (317). Only DAMGO stimulated secondary responses, however, since there was no effect for DPDPE on either field excitatory postsynaptic potentials or burst responses, indicating a presynaptic effect for it (317). It is possible that DAMGO disinhibits hippocampal CAI activity by activating mu receptors located on terminals of inhibitory neurons, since it depressed inhibitory postsynaptic potentials evoked in the presence of excitatory amino acid receptor antagonists (287). The responses of both DAMGO and DPDPE were blocked by the GABA antagonist bicuculline methiodide (317), suggesting an interaction of the GABA and opiate systems. The kappa agonists U-50,488H and U-54,494A reduced the magnitude of evoked CA1 population spikes after electrical stimulation of hippocampal slices, and either naltrexone or WIN44441-3, a kappa antagonist, attenuated the effect (444), as did a high concentration of calcium, indicating the action of the agonists might be due to their influencing calcium currents (408). The enkephalinase inhibitors thiorphan and SCH 32615 did not alter hippocampal field potentials, although they did potentiate enkephalin-induced epileptiform bursting, suggesting opiate mediation of the response (409). In the spinal cord, in general, opiate agonists suppressed electrical activity, although there were exceptions. Morphine inhibited C-fiber-evoked charges of the nociceptive neurons of the dorsal horn (253) and slowed responses to electrical stimulation of the dorsal root entry zone (326), although it increased responses in deeper laminae, indicating lamina-specific effects (326). Morphine, DPDPE, or DAMGO alone inhibited heatevoked activation of dorsal root neurons in the cat spinal cord (382), and ineffective doses of morphine, DADLE, or DPDPE, but not DAMGO, combined with an ineffective dose ofclonidine to produced a synergistic suppression of neural activity in the dorsal horn, suggesting an interaction between the adrenergic and opiate systems in this response (381 ). Support for this notion came from the report that opiates mediate many long descending adrenergic pathways but few descending serotonergic pathways at the spinal level (304). There may also be an interaction between enkephalins and the monamines on spinal reflex pathways, since the effect of DSLET was similar to that of clonidine or LDOPA (450). Both morphine and DTLET reduced activity of dorsal horn neurons in anesthetized rats, and their effects were potentiated by dibencozide, a coenzyme of vitamin B,2, suggesting potential

OPIATES: 1991 use clinically to lower the dose of morphine needed for analgesia (548). Although Met-enkephalin did not alter spontaneous discharge of trigeminal nuclear neurons or to evoked discharge to a light touch, it did attenuate evoked discharge to a noxious stimulus, indicating differential opiate effects on responsiveness of these cells (571). The enkephalin analog D A M G O modulated responses of the dorsal horn neurons to NMDA in a complex way that suggested an interaction between the two agents in nociception (440). As with mu and delta agonists, the kappa agonists tended to inhibit spinal activity. Dynorphin (425,488) and U-50,488H (425), but not dynorphin(2-13) (425), reduced dorsal root potential, and dynorphin also decreased ventral root potentials (488). Since dorsal root potentials reflect GABA-mediated presynaptic inhibition of primary afferent terminals, there is likely to be an interaction between the opiates and GABA (488). The kappa antagonist nor-binaltorphimine, but not the mu antagonist naloxone, reversed the effects of dynorphin and U-50,488H, so that the effect was kappa mediated (425). Support for that finding came from the report that U-50,488H inhibited prolonged nociceptive responses, and the effect was attenuated by naloxone at all ages but by nor-binaltorphimine only in rat pups, probably since kappa receptors are sparse in the adult rat spinal cord (497). Similar results were found in other parts of the nervous system. Morphine and D A M G O reduced spontaneous and evoked potentials from the tractus solitarius, and naloxone blocked their actions, indicating an opiate response. Neither dynorphin nor DPDPE, however, altered the potentials, so that the effect was probably mediated by the mu receptors (423). Morphine also inhibited the electrical activity of oxytocin neurons in the rat supraoptic nucleus (413), but the effect of the agonist on the firing rate of the bed nucleus of the stria terminalis was either stimulated or suppressed by application of morphine, with about half of the cells responding each way (108). The tibial nerve somatosensory cortical evoked potentials were unaffected by morphine, suggesting that opiate-activated spinal pathways do not interfere with transmission of afferent impulses resulting from electrical stimulation of peripheral somatic nerves (457). Morphine did, however, reduce in a naloxone-reversible way the electric organ discharge rate in Eigenmannia virescens(379), indicating that this type of sensory activity might be opiate mediated. Heroin increased the firing rate of some neurons and reduced that of others, with many of the former involving reward and most of the latter being associated with the limbic system. Its suppression of activity in parts of the hypothalamus suggested that there might be some neuroendocrine control of the opiate system (153). Although fentanyl had no effect on click-evoked amplitudes and latencies of action potentials in lateral olivocochlar efferent innervation, pentazocine increased the amplitude, indicating a stimulatory action of the kappa agonist (443). Application of DAMEA to the retina reduced responses to fullfield stimuli and increased responses to light spots, but [D-AIa2Leu]enkephalinamide had no effect (533). Enkephalins may act directly on sympathetic preganglionic neurons, since Met-enkephalin increased the activity of most of the ones studied, and the effect was reversed by naloxone (166). Since the opiate agonists generally suppressed electrical activity, it might be expected that the antagonists would have stimulated it, and that was the typical finding, suggesting that the endogenous opiate system may play a role in the modulation of such activity. Naloxone produced an increase in the total power of EEG waves in rats (175), and when it was applied topically to the caudate chemosensitive area on the ventral medullary surface of the brain, it potentiated neuronal activity of

1265 that area produced by hypercapnic breathing (523). Naloxone increased firing rates of neurons on the olfactory tubercle and paraventricular nucleus but decreased them in the cingulate and basolateral amygdala (153), indicating that the mediation of electrical activity by the endogenous opiate system is region specific. Opiate antagonists can also modulate amplitude and frequency of evoked potentials. Naloxone increased responses of the dorsal root to electrical stimulation (326) and visual evoked potentials along main and accessory visual pathways (432). Somatosensory evoked potentials were increased by naloxone, especially during cerebral ischemia (121), and the antagonist produced a dramatic increase in both evoked and spontaneous activity of the thalamic ventrobasal neurons in morphine-dependent but not morphine-naive rats (248), supporting the notion that the opiate system is altered in these situations. Naloxone did not, however, affect click-evoked amplitudes and latencies of action potentials in the chinchilla. Pentazocine, a kappa agonist and mu antagonist, increased these evoked potentials, but the effect was not reversible by naloxone (443), indicating that this action is probably not mediated by the opiate system. Similarly, neither naloxone nor nor-binaltorphimine changed the lumbar dorsal root potentials in the rat (425). Naloxone also did not alter muscle sympathetic nerve activity during rest, although it did potentiate the increase produced by isometric handgrip, indicating an inhibitory influence of the endogenous opiates on sympathetic nerve activity (138). Although, as indicated earlier, morphine lowered the electric organ rate discharge in Eigenmannia virescens, and although naloxone blocked that effect, the antagonist alone had no effect on that unique kind of electrical activity (379), suggesting that the behavior was not under typical regulation of the opiate system. The opiate system also seems to be involved in the modulation of sleep, as evidenced by the finding that morphine or nalmefene induced drowsiness or sleepiness (152). Morphine also suppressed rapid-eye-movement (REM) sleep in decerebrate but not in normal cats. The nature of the REM state was altered somewhat by morphine in both kinds of subjects, with more bodily movement, open eyes, and retraction of the nictitating membrane with the opiate (114). It also produced an initial suppression of non-REM (NREM) sleep, as characterized by a decrease in delta waves, followed by a strong rebound effect (100). Not surprisingly, naloxone increased delta wave activity (175). The antagonist also prolonged time awake, reduced total time asleep, and decreased percentage of time in the first stage of sleep, suggesting some regulation of sleep cycles by the opiate system (176). Further support for that notion came from the report that CTOP, the somatostatin analog with mu antagonist activity, reduced percentage of time in REM sleep and the duration of muscle activity during sleep, although the effect was seen only in early infancy (459). In the modulation of electrical activity, the endogenous opiates seem to interact frequently with the dopamine system, as seen by the fact that ICV administration of B-endorphin increased dopamine release (479). Administration of DPDPE, DAMGO, or CTOP to the ventral tegmental area also increased concentrations of dopamine in the nucleus accumbens, indicating that both mu and delta receptors are involved in opiate disinhibition of the mesolimbic dopamine neurons (118). Morphine enhanced dopamine release in the rat in the olfactory tubercle, nucleus accumbens, prefrontal cortex, and pyriform cortex but not in the striatum, suggesting that mesolimbic and mesocortical dopamine projections can be activated by the opiate system and can produce changes in cortical function that may be involved in some of the complex behavioral actions of the opiates (570). Acute morphine produced a naloxone-reversible increase in the

1266 discharge rates of type A dopamine neurons and a decrease in the spontaneous discharge rates of type B dopamine neurons (386), supporting the idea of an interaction between the two systems. The electrically evoked release ofdopamine was not affected by /3-endorphin (454), however, and neither DPDPE nor DAMGO, when microinjected into the striatum or nucleus accumbens, altered spontaneous release ofdopamine, but DPDPE potentiated potassium-stimulated dopamine release, so that delta receptors might be involved in the activity of the dopaminecontaining pathways (394). Activation of kappa receptors by U50,488H inhibited all dopamine neuronal systems in the brain, but this effect was evident on the basal activity of only the tuberohypophysial dopamine neurons and required activation of the other neurons to be seen (333). Depolarization of horizontal cells from the retina due to application of DAMEA was inhibited by haloperidol, suggesting opiate involvement with dopamine in the response (533). Lesions induced by 6-OHDA increased striatal proenkephalin mRNA on both the ipsilateral and contralateral sides and augmented dopamine 02 receptor mRNA on the ipsilateral side, so that striatal enkephalinergic activity may actually be under a set of controls that are more complex than a simple inhibitory influence by dopamine acting through its D2 receptors (79). The opiate system modifies other activities in the regulation of electrical functioning. The kappa agonist U-50,488H inhibited potassium-induced rise in synaptosomal free calcium concentrations, and the effect was attenuated by nor-binaltorphimine, indicating kappa receptor involvement (160). The agonist also depressed potassium-induced dynorphin B-like immunoreactivity from mossy fiber synaptosomes, further supporting the idea that dynorphin peptides interact with kappa receptors to autoregulate the excitatory mossy fiber synaptic input (160). Superfusion of slices of spinal cord with DAMGO or DPDPE, or the morphiceptin analog PLO 17, produced a decrease in potassium-evoked Met-enkephalin-like material, so that mu and delta receptors are involved in local presynaptic autoinhibitory control of the release of the material (65). A subset of dorsal root ganglion sensory neurons inhibited calcium currents in the presence of mu ligands (456), indicating possible tonic control by the opiate system. The endogenous antiopiate FMRFamide and its close relative FLRFamide activated calcium channels that carried sodium and barium currents in the presence of the peptides in the isolated heart ventricle, suggesting a possible regulatory mechanism for heart regulation (70). Morphine-exposed neurons showed a twofold increase in cholera toxin-catalyzed ADP-ribosylation and a 50% decrease in pertussis toxin ADP-ribosylation. Since cholera toxin selectively ADP-ribosylates G-proteins, the finding suggests that the increase in neurotransmitter-stimulated adenyl cyclase activity is caused by an enhanced functional role of G-proteins in neuronal membranes (539,541). Acute C-fiber, but not A-fiber, primary afferent stimulation depletes dynorphin in the ventral horn, a finding that can be interpreted to indicate that spinal dynorphin neurons may serve both as modulators of nociceptive input and as interneurons in motor reflexes (264). A specialized form of electrical activity in vitro that is opiate modulated is contraction of the guinea pig ileum to electrical stimulation. It is a standard preparation that measures opiate activity by the degree of inhibition of the contractions. As expected, morphine (258,339),/~-endorphin (258), Met-enkephalin (339), and dynorphin derivatives (266) blocked the contractions. Chronic morphine made the preparation tolerant to morphine, DAMGO, DADLE, and DSLET, but not to U-50,488H, so that there was cross-tolerance to mu and delta ligands but not to a kappa one (292). Incubation of the ileum with salmon calcitonin

OLSON, OLSON AND KASTIN potentiated the effects of morphine and Met-enkephalin, suggesting an upregulation of the opiate receptors by the calcitonin (339). The dynorphins (266), like morphine (78), also inhibited contractions of the vas deferens, another standard preparation. Naloxone reversed the inhibitions, but there were strain differences among the animals, suggesting genetic variations in their opiate systems. The opiates, therefore, modulate a wide variety of electrical responses. GENERAL ACTIVITY AND LOCOMOTION

Interest in the modulation of the level of general activity by the endogenous opiate system increased in 1991, with little difference in the findings. The opiate agonists typically decreased activity in a naloxone-reversible manner at high doses (345) and increased it at lower doses (452). It is probable that the opiate system, however, does not exert a tonic effect on activity, since opiate antagonists had little effect on activity (84,193,510) or responsiveness to stimulation, as measured by the acoustic startle response (501). A small dose ofnaloxone did, however, increase swimming speed in rats (347), and naltrexone reduced hyperactivity of autistic patients (23), supporting previous findings of opiate mediation of the disorder, at least in part. In this area of research, locomotion received the most attention, with a variety of agonists and antagonists being studied. In most cases morphine increased locomotion (69,154,282, 386,567), although at a high dose it suppressed locomotion (566). Injection of morphine into the VTA stimulated locomotion (154,567), and the effects increased with repeated testing, rather than tolerance developing (567). Lesions in the habenular nuclei (154) or administration of diazepam or pentobarbital (282) did not alter this activation by morphine, but naloxone (282,386) or fructose (69) blocked it, and ethanol enhanced it (282), indicating a complex relationship between the agonist and locomotion. Buprenorphin had results similar to those of morphine, with ethanol enhancing its effects and naloxone reversing them, but benzodiazepines not altering the ambulation-increasing effect of buprenorphine (282). The enkephalin analog DAMGO produced locomotion when administered into the ventrolateral striatum (28), the ventral pallidum (208), or the VTA (265), but ICV injection had no effect (519,531), and microinjection into the nucleus accumbens had a biphasic effect, first inhibiting and then stimulating locomotion (28). Similarly, DPDPE increased locomotion after injection into the ventral pallidum (208), the ventrolateral striatum (28), or the nucleus accumbens (28) and produced no effect after ICV administration (519), although another study reported an increase in both horizontal and vertical movement after ICV injection (368). Although ICV DADLE had no effect on linear locomotion in one study (532), horizontal motion increased and vertical movements decreased after ICV DADLE in another study (368), so that inconsistent results are frequent. Other mu ligands, including DSLET and DTLET, also produced findings of opposite effects on horizontal and vertical motion (368), but the delta agonist [D-Ala2]deltorphin (363,368), like DPDPE, stimulated both motions, indicating delta receptor selectivity for the response. The kappa agonist U-50,488H also produced contradictory results, decreasing locomotion when injected into the ventral pallidum (208,515), but increasing activity after chronic administration, indicating the development of tolerance (515). The peptide had no effect on locomotion when injected directly into the nucleus accumbens or ventrolateral striatum (28). Administration of a low dose of/3-endorphin ICV stimulated locomotion in rats, but a high dose inhibited it (480). The enkephalinase inhibitor acetorphan increased locomotion in normal

OPIATES: 1991 rats, but had no effect in those that had received chronic thiorphan, another enkephalinase inhibitor, indicating cross-tolerance (66). No tolerance, however, developed for the locomotor effects of the mu agonist levorphanol (515), so that tolerance was probably receptor specific. Contradictory findings have also been reported for the action of the opiate antagonists on locomotion. Naloxone decreased both fine and gross locomotion when given chronically (230), and chronic naltrexone inhibited locomotor activity (515), but acute naltrexone suppressed it only if the animals had previously been given restraint stress (524). Ethanol blocked the effect of restraint, and naltrexone reversed the blockade (524), suggesting a complex interaction between stress, ethanol, and the opiate system. Other antagonists, including/3-funaltrexamine (519,566), ICI 154,129 (515), and the endogenous antiopiate MIF- l (269), failed to alter locomotor behavior, as had the acute naltrexone under normal conditions (524), creating doubt concerning the physiological role of the opiate system on locomotion. Naloxone did, however, affect some induced changes in locomotion, such as blocking the stimulation of it by scopolamine (554) or by nitrazepam, both chronically and acutely (374). A high dose of the antagonist potentiated the inhibition of mobility by inflammatory pain, but a low dose did not affect it (354). Coadministration of naloxone and the a2-noradrenergic antagonist yohimbine produced locomotion (268), suggesting an interaction between the opiate and adrenergic systems. The increased activity produced by morphine was antagonized by ICI 154,129, although the antagonist had no effect itself (566), suggesting that the opiate system may not play a role here even though exogenous opiates can facilitate the response. It appears that the effects of opiates on locomotion are mediated in part by the dopamine system, since DAMGO antagonized the increase in locomotion produced by the dopamine DE-selective agonist RU 24213, an effect that was in turn blocked by the mu antagonist ~-funaltrexamine (519). The increased activity produced by ~-endorphin occurred only at doses that produced dopamine release, suggesting dopamine was critical for the expression of this behavior (480). Similarly, morphine's stimulation of locomotor behavior was accompanied by an increase in the discharge rates of type A dopamine neurons from the substantia nigra and a decrease in firing of type B neurons (386). Indirect evidence for dopamine activity came from the finding that the GABA agonist baclofen inhibited DAMGO's increased locomotion, an effect that was reversed by 6-OHDA lesions of the nucleus accumbens (265). In addition to locomotion, other forms of activity have been studied for their mediation by the opiate system. Circling is one of these behaviors. Unilateral administration of morphine into the VTA (516) and DAMGO or DPDPE into the ventral pallidum (208) produced contralateral circling, although the latter induced it only at high doses. There was no effect for U-50,488H, indicating kappa receptors were not involved (208), nor was there any circling produced by ICV DAMGO (519,531 ), DPDPE (519), [D-Pen2,L-PenS]enkephalin (DPLPE) (532), or DADLE (532). Circling induced by apomorphine was not affected by the enkephalin analogs either (531,532), and the response threshold for circling behavior elicited by electrical stimulation of the PAG was not altered by DPDPE, U-50,488H, or morphiceptin (463). Circling elicited by the dopamine agonist RU 24213 was antagonized by DAMGO, however, indicating opiate mediation of the response (519). Similar results to those for circling were reported for rearing and grooming, with deltorphins increasing rearing and naloxone and naltrindole abolishing the effect (363). No rearing or grooming was induced by DAMGO (519,531), DPDPE (519), DADLE (532), and DPLPE (532), and both behaviors produced by RU

1267 24213 were antagonized by DAMGO but not by DPDPE (519). Of the enkephalin analogs only DAMGO (531) antagonized apomorphine-induced grooming, but both DAMGO (531) and DADLE (532) blocked apomorphine-induced rearing. Grooming induced by SKF 38393 was reduced by the kappa ligands U50,488H and U-62,066E, suggesting that kappa receptors might be involved in the response (337). Pentazocine increased both grooming and rearing (123), suggesting possible mediation of the responses by the opiate system, and naloxone or a Dl antagonist inhibited grooming induced by neuromedin, a bombesin-like peptide, suggesting partial mediation by the opiate and dopamine systems (542). High levels of stereotyped licking and gnawing were produced by morphine in rats with lesions in the habenular nuclei, indicating that the nucleus does not have a role in these responses (154). Atypical biting and chewing, however, were found after injection with yohimbine and naloxone (268), so that some opiate mediation of the effects was seen. Deltorphins increased sniffing behavior in rats, and it was antagonized by natrindole or high doses of naloxone (363), suggesting primarily delta receptor actions for the response. Both opiate and nonopiate effects were probably involved in the stimulation of exploration, leaning, and digging by pentazocine, since naloxone potentiated the exploration but had no effect on the other behaviors (123). The yawns induced by apomorphine, however, were probably not mediated by the opiate system, since naloxone had no effect on them (373). Some stereotypies might be mediated in part by the opiate system, since dopamine-induced oral stereotypies were blocked by concomitant administration of naloxone, and if they were allowed to be expressed, the antagonist could attenuate them (402). Quinpirole-induced stereotypies were reduced by U50,488H and U-62,066E, suggesting involvement of the kappa receptors in the response (337). The mechanism by which stereotypies work might be a downregulation or upregulation of the opiate system. Stereotypies might occur because they have some rewarding value, and that reward might increase opiate activity. If the stereotypies activate the endogenous opiate system, the animals engaged in them should show hypoalgesia or analgesia when tested, but hyperalgesia was found, suggesting that the behavior lowers stress and the opiate peptides (111). An extreme form of opiate suppression of activity is catalepsy, characterized by muscle rigidity. Many opiate agonists have been shown to produce catalepsy, including morphine (15,375), ~endorphin (480), dermorphin (167,553), alfentanil (364), fentanyl (295), etorphine (295), and methadone (15). The nicotinic antagonist mecamylamine potentiated and prolonged morphine's catalepsy, but it inhibited that of methadone, possibly through striatal dopamine metabolism (l 5). Dopamine might also mediate fl-endorphin-induced catalepsy, since the severity of the rigidity was related to release of dopamine in the nucleus accumbens (480). Alfentanil-induced muscle rigidity was antagonized by ~-funaltrexamine and naloxonazine, implicating mu receptors in the response (364). Naloxone (167) or SK&F 86466 (553) reversed the effect of dermorphin, providing further support for the role of the mu receptors in opiate catalepsy. Administration of morphine into the periaqueductal gray produced periods of catalepsy alternating with periods of explosive motor behavior (375), suggesting opiate mediation of both responses. Fluctuation of motor effects induced by the opiates was also found after fentanyl and etorphine, going from catatonia to paralysis and back to catatonia. Naloxone reversed the catatonia, but when naloxone was given during the paralysis, it did not prevent the occurrence of catatonia, indicating that catatonia was a necessary stage to and from the paralysis (295). Catalepsy induced by SCH 23390 was potentiated by U-50,488H and U-

1268

OLSON, OLSON AND KASTIN

62,066E, but raclopride-induced catalepsy was not affected (337), indicating that some forms of the muscle rigidity are opiate mediated and others are not. In past years there was speculation about the possible involvement of the opiate system in effects of strenuous exercise, but the evidence has been contradictory. Exercise increased the concentration of ¢/-endorphin in plasma ( 129,169,187,307,514) but not of Met-enkephalin or Leu-enkephalin (187). The level of training was not important, since the change in the peptide was the same in trained and untrained cyclists (169). Accompanying the rise was an increase in the threshold for pain, although there was no significant correlation between them. Although naloxone had no effect on the pain,/3-endorphin increased more with naloxone than with saline (129). Anginal pain in coronary patients, however, was related to a blunted or absent response ofl3-endorphin to exercise (307), leaving the nature of the role of the endogenous opiates in exercise unclear. The intensity of the exercise was critical, since the rise in plasma/3-endorphin correlated with the severity of the exercise. There was no increase until the cyclists reached a minimum of 70% VO2n~ (169). Acute exercise in rats also activated the opiate system, with changes depending on extent of exercise, the peptide measured, and where it was measured. After 4 hours of swimming, there was a decrease in 13-endorphin in the pituitary and hypothalamus, no change in it in the adrenals, and an increase in c~-and "r-endorphin in plasma. Seven days of swimming produced increases in a-,/3-, and 3,-endorphin in the pituitary, increased c~- and /3-endorphin in the adrenals, and decreased ~-endorphin but increased ~/-endorphin with no change in a-endorphin in the hypothalamus (514). Naloxone given after submaximal treadmill exercise had no effect on the resulting cardiovascular responses, but when the antagonist was given before activity began, it attenuated the rise in heart rate due to the exercise even though it did not alter basal heart rate (143). It is possible, therefore, that the opiate system is activated during strenuous exercise. The endogenous opiates do not seem to regulate melatonin in athletic women, however, since naloxone had no effect on it, regardless of menstrual status. Nocturnal melatonin, though, had a twofold increase in active as opposed to sedentary women, but only in amenorrheic individuals (289). The meaning of this finding is unclear, and the role of the opiates in exercise remains to be delineated. SEX, PREGNANCY, AND DEVELOPMENT In 1991 there continued to be interest in the possible modulation of sexual behavior by the opiate system, although definitive answers were not yet found. In females the mu agonists, morphine (173,544) and D A M G O (395), tended to inhibit lordosis, but the kappa agonists, DPDPE and U-50,488H (395), facilitated it in ovariectomized rats given progesterone and estrogen. The suppression of lordosis by DAMGO did not occur in the presence of estrogen alone, but that by the kappa ligands did, indicating the latter was independent of progesterone and the former was dependent on it (395). The inhibition by morphine was blocked by pretreatment with naloxone and occurred with either systemic injection or bilateral infusion into the ventromedial hypothalamus (VMH), and since mating produced both lordosis and a release of norepinephrine in the VMH that were morphine reversible, it was suggested that the primary site of action might be the hypothalamus (544). The endogenous antiopiate MIF-1, but not Tyr-MIF-1, facilitated female sexual behavior, and its effect was dependent on progesterone, just as DAMGO's was, but since MIF-I did not reverse the morphineinduced inhibition of lordosis, it was suggested that MIF-1 was not acting like an opiate antagonist (173).

Since the symptoms of premenstrual syndrome (PMS) mimic those of withdrawal, it could be that PMS is due to a withdrawal or decrease of endogenous opiate activity, which produces depression and fatigue (120). Support for this idea came from the reports that there are changes in opiate inhibition ofluteinizing hormone with the menstrual cycle, that in ovariectomized animals/3-endorphin is low and that estrogen replacement increases the opiate, that the severity of symptoms of PMS is correlated with concentrations of plasma/3-endorphin, and that ~endorphin decreases premenstrually more in women with PMS than in normals. The deficiency in the opiate may produce premature release of luteinizing hormone, which results in symptoms of PMS (120). Morphine inhibited the estrous cycle in opiate-naive rats, and morphine-dependent females briefly became acyclic, then returned to normal (322), providing additional evidence for a role of the opiate system in the menstrual cycle. In males, as in females, morphine inhibited sexual behavior (173), but unlike females, males also had suppression of it by the kappa agonist U-50,488H when administered into the VTA or nucleus accumbens. It produced no effect in the medial preoptic area, however (302). Naloxone inhibited sexual activity (268), but MIF-1 had no effect on it, and the endogenous antiopiate did not alter morphine-induced suppression of the behavior, indicating that it was probably acting like a metabolite of oxytocin rather than like an opiate antagonist (173). Naloxone reversed the decrease in copulation induced by yohimbine but did not affect the noradrenergic antagonist's lowering of the number of ejaculations to exhaustion, so that the two agents did not produce consistent results (268), leaving questions about the role of the opiate system in sexual behavior. Penile erection produced by apomorphine was suppressed by the enkephalinase inhibitor acetorphan, but acetorphan's action was not reversed by naloxone, indicating that the endogenous opiate system was probably not involved (373). Administration of naloxone before ejaculation did not interfere with a drastic reduction in burying behavior after ejaculation, suggesting that opiate mechanisms are not involved in this antinociceptive action associated with mating behavior (141). Chronic stressing by restraint decreased testicular function and increased pituitary /3-endorphin, but naltrexone did not alter the lowering of testosterone, so it was probably not mediated by the change in/3endorphin (315). Naltrexone did potentiate the elicitation of ejaculation by MDMA, however, indicating that the opiate system might mediate this behavior (57). Repeated exposure of males to bedding of estrous females, but not of males or ovariectomized females, produced a naloxone-reversible increase in electrochemical signals from electrodes implanted in the nucleus accumbens, suggesting an opiate contribution to the activation of the mesolimbic dopaminergic system to these sexually relevant stimuli (357). Monthly measurements of concentrations of Leuand Met-enkephalin in ganglia of the periesophageal ring in the terrestrial snail (Helix aspersa) revealed seasonal peaks in the spring and autumn, when reproduction occurs (184), implying that the opiate system might regulate that behavior. The contradictory findings, however, do not allow any definitive conclusions about what role opiates might play in sexual activity. The opiate system does seem to be involved in development, from embryonic stages through senescence. Mu and kappa receptors are detected by gestation day 14, but delta receptors cannot be seen prenatally in mouse brain (427). Human placental villous tissue, however, contains kappa receptors that regulate acetylcholine and hormone release and increase in number with gestationat age. Use of opiates during pregnancy affects the number and function of the receptors (14). Dynorphin (14,427,428), 13-endorphin (14,427,428), Met-enkephalin (14, 427,428), and Leu-enkephalin (14) can first be detected as early

OPIATES: 1991 as embryonic day 11./3-Endorphin is also found in sheep placenta, and it, like enkephalin, increases with age, but its function in this situation has not yet been discovered (113). Similarly, in the rat /3-endorphin and hypothalamic mu receptors increase during pregnancy, especially at the end of it, and return to normal quickly after delivery (126). In rabbits, Met-enkephalin also occurs early and progressively increases during development (341). The developmental changes in opiate binding in sheep fetuses correlate with changes in HPA axis activity, suggesting these changes may contribute in part to the altered ACTH response to exogenous opiates that occurs. The maturation of the HPA axis may be responsible for the onset of parturition (572). Support for the role of the opiates in late gestation came from the report that administration of naloxone to block the opiates reduced plasma concentrations of ACTH (73). Low doses of morphine inhibited electrical activity of oxytocin neurons in the rat supraoptic nucleus, and sensitivity of the neurons to morphine decreased with chronic morphine and with increased activation on cessation of the opiate. Such a sequence has been postulated to take place with the endogenous opiates and oxytocin neurons during pregnancy (413). Fetal alcohol exposure increased brain concentrations of/3endorphin, and in those animals, administration of naltrexone accelerated sexual maturation, indicating that such an event may affect the development of the opiate system, which in turn has other developmental ramifications (104). Cocaine during pregnancy likewise increased opiate receptor binding in higher regions of the brain, but not in the diencephalic or brainstem regions in weanling offspring, with possible implications for developmental delay or cognitive and motor dysfunctioning (93). Support for that idea came from the finding that infants from methadone-maintained mothers had immature nervous systems, as manifested in reduced opiate receptors and neurotransmitter activity (124). Conversely, upregulation of the opiate system by prenatal stress produced a higher birth weight, faster returning to the home cage in a nest odor discrimination task, and increased exploratory behavior in a complex maze, suggesting that this weak stimulation of the opiate system actually facilitated these functions (506). A role for the endogenous opiates is proposed in analgesia that occurs in pregnant rats on day 21 of gestation and postpartum days 1 and 3, since a high dose of naloxone reversed the effect and since nonpregnant animals were not affected by that dose of the antagonist (222). There was a rise in/3-endorphin in human mothers at the induction of general anesthesia before cesarean surgery, probably related to the stress of the procedure, however, rather than to prepare for delivery, since there was no corresponding rise in patients receiving an epidural anesthetic (418). There is also upregulation of the opiate system of the infant during birth, since their plasma/5-endorphin increased after cesarean delivery, and the rise was negatively correlated with respiratory function, showing that the concentration of the peptide increases in response to stress, especially hypoxia (418). The concentration of/3-endorphin was also greater in sick newborns than in well ones, and premature infants had higher concentrations than term ones, regardless of health, providing further support for stress in neonates causing release of endogenous opiates (297). Plasma Met-enkephalin also was higher in newborns than in adults, whether delivery was cesarean or vaginal and whether it was measured in the umbilical artery, the umbilical vein, or in the infant's plasma (340). The enkephalin progressively increased during gestation and dropped rapidly after birth (341), but its concentration was not associated with gestational age or health status of the infant, leaving the significance of the finding unclear (340). It also is likely that the endogenous opiates are

1269 involved in antinociception in infants shortly and briefly after cesarean, since milk delivered to the tongue of the rat pup produced a naloxone-reversible analgesia equal to that of morphine, even though the pups had never been exposed to maternal contact and had never suckled. Apparently the milk was a calming substance that produced opiate reward (60). Placental opioid-enhancing factor (POEF) found in amniotic fluid and placenta potentiates morphine-induced analgesia (2,122,278) but not nonopiate analgesia (278). It is effective when eaten but not if injected intraperitoneally (IP) or SC (2). It appears to work centrally, because systemic quaternary naltrexone had little effect on the enhancement of morphine analgesia by POEF, but ICV injection of the antagonist blocked its action (122). Some tolerance develops to the effect of POEF, which is not surprising due to its opiate nature, and it appears to act by facilitating opiate binding rather than by triggering release of additional opiate peptides (278). Placental opioid-enhancing factor enhances maternal behavior as well as analgesia (278), but it does not modify morphine-induced hyperthermia (2). Maternal behavior does seem to have some component of opiate regulation, since/5-endorphin increased the mother's latencies to retrieve pups and decreased the percentage of rats displaying full maternal behavior ( 139,140,331). The peptide's effect was blocked by CCK-8, indicating that it can act like an opiate antagonist in this situation (139,140). In addition to 15endorphin, morphine and DAMGO inhibited maternal behavior, with DAMGO producing the strongest suppression, but DPDPE, U-50,488H, and SKF 10047 did not alter it (331). Lactation might be opiate modulated, since ~-endorphin decreased during it (126), but Met- and Leu-enkephalin were high during nursing. Met-enkephalin decreased rapidly when the mother left the litter and quickly increased after the mother-young reunion, but Leuenkephalin did not change unless the separation was prolonged. The exact role of enkephalins in lactation, however, is not clear (147). Maternal deprivation affected the rat pups, too, suppressing lung DNA synthesis in a naloxone-reversible way, suggesting an opiate effect (177). There is a population of cells within the germinal zone of the neonatal rat forebrain with immunoreactivity for/3-endorphin and pro-opiomelanocortin (POMC), which is present at birth and disappears by the sixth day. The cells may synthesize POMC, which is further processed into/3-endorphin and may, therefore, have a role in neural development (316). A recently discovered opiate growth factor, identified as Met-enkephalin, acts as a regulatory peptide for the development of the nervous system. Its binding capacity increases from birth to day 10 in the rat cerebellum and it is not detected at weaning, which is consistent with the timetable for cerebellar neurogenesis (346). It interacts with the zeta receptor to modulate growth processes (346,580). The unique zeta receptor is not restricted to development of the nervous system, although in the adult, its functions appear to be nonneural, as in metastatic carcinoma (580). In the embryo it does not interact with G-proteins, but it does in the adult, suggesting that it may control cell growth and differentiation (33). Proenkephalin mRNA and Met-enkephalin were first detected in the rat hippocampus at the fifth day postnatally, with the proenkephalin mRNA being primarily in the CA1, CA3, and dentate gyrus regions. By the tenth day, there was an increase in the CA 1 and CA3 regions and a decrease in the dentate gyrns; the levels remained constant after that, suggesting that the enkephalinergic system develops postnatally in the rat hippocampus (478). Similarly, the ontogeny ofproenkephalin m R N A expression in Purkinje cells of the rat cortex was developmentally regulated, since levels of expression closely followed the chronological order of settling and maturation of these neurons (385).

1270 In principal ganglion cells, enkephalin immunoreactivity is present by the third postnatal week but disappears by the eighth week, although the population density of ganglion cells expressing preproenkephalin mRNA is similar at both ages, indicating that posttranscriptional downregulation ofgene expression is involved in the disappearance of enkephalin immunoreactivity at these sites in the adult (555). Newborn rats receiving repeated injections of morphine showed no tolerance until the ninth postnatal day, suggesting a rapid proliferation of opiate receptors in the first 2 weeks of life (538). High concentrations of proenkephalin mRNA and enkephalin were detected in immature cells identified as astrocytes in the cerebellum and cerebrum, indicating the gene expression by these astrocytes is important during CNS maturation (196), and suggesting that Met-enkephalin mediated DNA synthesis in the astrocytes (490,581). In the ventral horn of the rat spinal cord, enkephalin-positive fibers increased with development up to day 28, then leveled off, further supporting the role of the opiate peptide in development (388). The ability of opiates to modify glial growth is highly selective and varies depending on astrocyte type, as well as temporal and regional factors (197). Morphine produced a naloxone-reversible reduction in glial cell production and induced differentiation ofastrocytes, further supporting the opiate modification of neural growth (489). Other than Met-enkephalin, only des-Met-enkephalin and peptide F, among the many other opiate peptides tested, including ligands of all kinds of receptor types, affected DNA synthesis in the rat (581). In the mouse cerebrum, opiate changes in CNS growth are the result of primarily delta receptors, since the delta ligands DPDPE and Met-enkephalin decreased the number ofglial cells, but the mu agonist DAMGO and the kappa ligand U-69,593 had no effect (490). Although kappa and mu receptors are found in the developing rat cerebellum, kappa, mu, and delta receptors are found in the adult (580), confusing the picture. There is a change in the distribution of receptors in the cerebellum with age, with infants having high concentrations of the opiates in the external granular layer and less in the internal granular layer, but children and adults having negligible opiate receptors in the internal layer (260). The involvement of 13-endorphin in development is not clear, since its concentrations in CSF were not correlated with age (191). Hypothalamic ¢]-endorphin deceased in disease-free aged mice, although some old animals with pituitary tumors had no loss of the peptide, suggesting a subpopulation of/3-endorphin neurons that either die or stop producing the peptide in the aged (355). In mononuclear PBMC cells in the rat or human,/3-endorphin increased with age, and polyclonal stimulation decreased it. The age-related modifications of it could play a role in immunodepression in the aged (441). In early development, 13-endorphin appears to be involved in brain and liver DNA synthesis, since the process is blocked by administration of the peptide in preweanling rats. Naloxone inhibited the action of t3-endorphin, and alone the antagonist increased DNA synthesis, suggesting a tonic effect of the opiate system on it. There were no significant effects by 20 days, however, indicating 13-endorphin affected these functions only in early development (37). Similarly, only in the first 2 postnatal weeks did 13-endorphin affect lung maturation, with its administration decreasing ornithine decarboxylase (ODC) activity, which regulates cell growth, multiplication, and differentiation. Plasma corticosterone was also increased by t3-endorphin, suggesting that its influence on lung maturation may be indirect, involving glucocorticoids in the action (178). It appears that hypothalamic 13-endorphin does not occur until later in development, since the peptide did not affect fear-motivated learning at 30 or 45 days but did at 60 and 90 days (367).

OLSON, OLSON AND KASTIN Modification of the endogenous opiate system occurs with early administration of morphine, producing a decrease in the density o f m u receptors in several brain areas. With longer treatment, there was no additional change, demonstrating the plasticity of the immature opiate system (513). Early chronic morphine also slowed physical development, decreasing body weight and postponing eye opening. Since coadministration of morphine and Tyr-MIF- 1 produced the same effect, Tyr-MIF- 1 was not acting like an antiopiate on these behaviors, but in measures of nociception it not only reversed morphine analgesia but also produced hypersensitivity to pain. The neonatal combination injection of Tyr-MIF-l and morphine significantly potentiated the effect of morphine alone on the transport of labeled TyrMIF-1 out of the brain on day 23. It appears that Tyr-MIF-1 can exert either opiate or antiopiate effects in different situations (30). Chronic morphine administered after weaning delayed sexual maturation in female rats as measured by first ovulation and vaginal opening (322). Morphine and U-50,488H produced a rise in corticosterone in the developing rat pup, demonstrating significant opiate receptor control of HPA function in early postnatal development (8). Chronic handling neonatatly produced an analgesia in the rats tested as adults that was acutely reversible by naloxone but not by MIF-1 and was potentiated by morphine. However, chronic administration of MIF-1 induced hypoanalgesia, blocking the effects of morphine when tested as adults and indicating changes in the developing opiate system induced by the chronic MIF-1 (106). Postnatal exposure of rat pups to methadone through lactating methadone-dependent mothers might have affected the opiate system, since the pups were delayed in expressing the righting response and in their ability to perform a vertical screen task, and their survival rate was lowered. They also had altered analgesic responses (134). Naloxone produced an intermittent increase in the mitotic index, especially in early neonatal weeks, of prenatally X-radiated brains of rats, revealing that repair of embroyotoxic X-radiation is normally under strong control of the opiate system (449). Exposure to 3-isobutyl-/-metbylxanthine (IBMX) during early infancy produced quasi-withdrawal in opiate subjects and attenuated morphine-withdrawal symptoms in adulthood, suggesting an alteration in the development of the opiate system by the IBMX (362). The neonatal rat brain had G-proteins and more opiate receptors sensitive to G-proteins than the adult brain, possibly because the newborn's intracellular sites contain newly synthesized receptors that together with G-protein are in route to the cell surface. This would explain some of the inconsistencies between measurements in vitro of opiate receptors from neonatal and adult brains (46). There was also a decrease with age after injection of U-50,488H or U-69,593 in responses of the dorsal horn neurons to innocuous stimulation, which might be accounted for by the scarcity of kappa receptors in the spinal cord of the adult rat. With noxious stimuli, the kappa agonists attenuated the nociceptive response, and the action was reversed in adults and pups by naloxone but in pups only by nor-binaltorphimine, further suggesting reduced kappa activity in the adult (497). The changes in the opiate system with age, therefore, are complex, and much additional work remains before an understanding of its role in development becomes clear. IMMUNOLOGICALRESPONSES There was increased interest in the possible interaction of the opiate system and the immune system in 1991, with no definitive answers concerning it. There were many instances in which the opiate peptides were shown to affect immune function,

OPIATES: 1991 but in some cases they suppressed it and in others they potentiated it, depending on a number of factors, including specific peptide, dose, and the measure of immune activity. Most studies using morphine reported inhibition of the immune system by the drug (75,86,102,144,186,309,410,461,557), although others found morphine-induced enhancement of it (86,186,389,392,410), and a few showed no effect for the morphine (186,481,557). Mitogen-induced lymphocyte proliferation was potentiated by morphine in vitro and suppressed by it in vivo (86), suggesting a possible explanation for the differential results. It was also the case that morphine impaired immune activity in spinal cord-injured rats, but in normals it had no effect or increased it (186), demonstrating the variability typical of the field. Similarly, morphine suppressed splenic but had no effect on mesenteric lymphocyte function (557), and in cancer patients reduced the already low natural killer cell activity but increased the elevated lymphokine activator killer cell activity, indicating differential effects of the opiate on different immune functions (410). A possible mechanism of opiate-induced immunosuppression might involve calcium, since morphine inhibited the increase in cytoplasmic free calcium induced by mitogens in mouse splenocytes (46 l). Conflicting reports on the role of adrenal activity in morphine's suppression of immune function occurred, with one study finding adrenalectomy or hypophysectomy had no effect on it as measured by peripheral blood lymphocyte proliferation to concanavalin-A (Con-A) in rats (144), but another showing an absence of Con-A- or lipopolysaccharide-stimulated lymphocyte proliferation after removal of the adrenals in mice, as well as reduction of atrophy of the spleen and thymus after surgery (75). Corticosterone seems to be important, since the reduction of anti-KLH (keyhole limpet hemocyanin) antibody production by morphine was correlated with an increase in the steroid, both in vitro and in vivo (309). Not only did morphine suppress immune function, but when the peptide was paired with a distinctive environment, the environment produced a morphine-like alteration of immune activity, indicating that classical conditioning may play a role in the response 002). The reverse was also reported, with infection with the Friend virus increasing morphine toxicity. Although chronic morphine before infection with the Friend virus had no effect on mortality from the virus, a single challenge with a large dose of the opiate, which was not lethal in noninfected controls, increased mortality markedly (up to 100%), suggesting that the virus increased morphine toxicity (481 ). In some cases, especially with tumor growth, morphine had a therapeutic effect, suggesting it might be useful in the treatment of malignancy. Morphine attenuated enhanced metastatic effects of surgery in rats (389) and reduced blood vessel proliferation in chick eggs (392). The effects of ~-endorphin seem generally more beneficial, with the peptide increasing immune function in a number of situations (26,86,92,165,358,387,392,534), although there were cases of suppression of immune activity (26,92,99,462) and of it having no effect (92,240,534). Mitogen-induced lymphocyte proliferation was potentiated by ~-endorphin both in vivo and in vitro (86), as was Con-A-induced proliferation (26). Preincubation with ~-endorphin increased proliferation ofT cells and interleukin-2, but continued presence of the peptide abolished the effect, and chronic/~-endorphin alone had no action on it (534), perhaps indicating tolerance to its ability to stimulate immune activity. In invertebrates, ~-endorphin was phagocytic (387), and it reduced blood vessel proliferation in chicken eggs, suggesting a possible mechanism for inhibition of tumors (392). Although B-endorphin was reported to increase natural killer cell activity in some cases (92,165,359), in others it had no effect (92,240). The ICV, but not systemic, injection of B-endorphin

1271 suppressed natural killer cell activity, an effect that was blocked by naloxone (212). Inhibitory effects of ~-endorphin were reported on activity of lympholike activated killer cells (92), in phytohemagglutinin (PHA)-induced proliferation of lymphocytes (26), and PHA-stimulated [3H] thymide uptake, an effect that was antagonized by N-acetyl-/~-endorphin, which itself had no action (462). Fatality of mice to the infectious agent tsG31 KS5 (a temperature-sensitive mutant of VSV) was increased by /~-endorphin, perhaps by suppressing T-ceU activity (99). Antiserum to ~-endorphin inhibited stimulation of natural killer cells by corticotropin-releasing factor (CRF), suggesting the opiate might be a link in the chain between CRF and the immune system. Corticotropin-releasing factor stimulates monocytes to produce interleukin-l, which in turn trigger the release of/3-endorphin, which then increase natural loller cell function (296). Since anti-/%endorphin antisera injected into prednisolone-treated mice suppressed normal recovery ofthymic immune activity, and pinealectomy (which removes melatonin) negated the effects of the antisera, it was proposed that the function of the melatonin-opiate network might be to drive a correct immune recovery after the depression caused by elevated corticosterone associated with immune responses (325). Although not as consistent, in general Met-enkephalin and its analogs, as did /3-endorphin, tended to facilitate immune function (86,165,216,225,447,466,482,483,545), but there were conflicting findings of it reducing immune activity (218,545,582) or of it having no effect (165,240,534). Mitogen-induced lymphocyte proliferation was potentiated both in vivo and in vitro by DAMEA (89), and the opiate peptide increased adherence and migration of immunoactive cells (447), produced formation of interleukin-l-like molecules (483), stimulated activity of hemocytes (466), and produced activation of immunocytes (216) in Mytilus edulis. Both Met-enkephalin and Met-enkephalinArg6-Phe7 stimulated the immune system of M. edulis and humans, although with different time courses, and the enkephalinase inhibitor phosphoramidon potentiated the effect of the analog (482), indicating opiate modulation of immune activity over a wide range of species. The ability to recover thymic cellularity and to mount a primary antibody response against T-dependent antigens was inhibited by anti-Met-enkephalin antisera, suggesting possible facilitation of these immune functions by Met-enkephalin (325). After prestimulation with a low dose of polyinosicinic:polycytidylic acid, Met-enkephalin or glycyl-glutamine (which reflects the carboxyl-terminal end of/~-endorphin) enhanced natural killer cell activity of mice, but had no effect in non-prestimulated mice. This effect was not naltrexone reversible, implying that the opiates might mediate immune function indirectly, reacting with other accessory cells, which in turn released stimulators of the natural killer cells (165). The incidence and severity of experimental allergic encephalomyelitis were mediated by Metenkephalin, with a high dose of peptide increasing them and a lower dose reducing them and also reducing inflammatory lesions in the brain (545). Similarly, enkephalinase inhibitors exerted dose-dependent opposite effects after inoculation with sheep red blood cells, increasing the immune response at low doses and decreasing them at high doses (225). Although most studies had reported that DAMEA facilitated immune function, an ultra-low dose of it inhibited production of respiratory burst in human neutrophils, with an inverse bellshaped dose-response curve, which was partially blocked by naloxone (582). Chronic Met-enkephalin, likewise, was shown to increase the incidence of colon tumors after azoxymethane, and naloxone attenuated the effect, suggesting that the response was opiate mediated (218), but T-cell culture was unaffected by the continuous presence of Met-enkephalin (534).

1272 Other opiate peptides seem to have little role in immune function, since chronic a-, "y-endorphin, and Leu-enkephalin had no effect on proliferation ofT-cell culture (534). In M. edulis, Leu-enkephalin also produced no immune response (447), but the enkephalin had a bidirectional modulation of natural cytotoxic activity in spleens of mice, first reducing, then increasing natural killer cell activity. The early inhibition was naloxone reversible, but the later stimulation was not, indicating some opiate and some nonopiate modulation of the response (155). Beta-casomorphin, a milk-derived peptide with opiate-like properties, inhibited a wide variety of immune functions in a naloxone-reversible way, suggesting the peptide was probably acting through opiate receptors (133). The possible role of the endogenous opiates was also investigated by the use of antagonists to modify immune activity, with inconclusive results. Although naloxone had no effect on cytotoxic activity in the spleen (155) and no effect on tumor growth (218), naltrexone reduced tumor growth (5) and was associated with increased T-cell proliferation (512). Naltrexone also inhibited corticosterone-induced suppression of immune function, and since systemic administration of quaternary naltrexone, which only acts in the periphery, had no effect, it was suggested that the response does not directly affect lymphocytes but modulated the sympathetic output responsible for alteration of the immune response (321). Chronic naloxone increased antibody production in the spleen and natural killer cell activity (87), suggesting tonic opiate inhibition of the response. Involvement of the opiate system can also be seen by changes in it during immune activity. /3-Endorphin is synthesized in lymphocytes and influences their activity (26), and in morphinedependent individuals, there is an increase in/3-endorphin content in the thymus and spleen (26), suggesting opiate mediation of immune functions. Interleukin-1 stimulated release of/3-endolphin pituitary cultures, and interleukin-l enhanced CRF stimulation of/3-endorphin release (135), further implicating an interaction between the opiate and immune systems. The circadian rhythms of natural killer cell activity and/3-endorphin are similar, peaking in the morning, with minimum and medium daily concentrations of the peptide correlating with natural killer cell activity (358). Tumor development was associated with decreased /3-endorphin in the hypothalamus, and naltrexone blocked the loss of the peptide, suggesting that the response was mediated through the opiate receptors (512). Lower plasma/3-endorphin predicts persistently low natural killer cell activity, which in turn predicts higher illness morbidity, especially in younger subjects (300). In the aged, too, modification of B-endorphin in mononuclear cells could play an indirect role in immunodepression, perhaps through an inhibitory action of the peptide on the thymus, causing atrophy of the organ (44 l), although the immunoreactivity in human peripheral blood mononuclear cells did not represent authentic ct-, ~,-, or/3-endorphin, since the radioimmunological assay found no match for them (543). Interferon-c~ inhibited opiate ligand binding to brain membranes, suggesting a possible mechanism for a communication network between the CNS and the immune system (350). There were, in addition, kappa binding sites on routine lymphoma cells, which shared many properties with brain kappa receptors (291), but no opiate receptors were found in nonneural human tumor from renal and colon carcinoma and sarcoma (45). In human small cell lung carcinoma, there was preprodynorphin, as well as preproenkephalin mRNA, suggesting the opiate peptides might have an effect in it (163). Taking a more specific look at cancer, it can be seen that the opiate system may play a role. There was decreased/3-endorphin binding, correlated with lower natural killer cell activity in cancer

OLSON, OLSON AND KASTIN patients, especially in depressed ones (324,583), and exercise increased both (583). A decrease in hypothalamic ~-endorphin in stressed rats was correlated with an increase in the number of tumors developed, and the loss of the peptide was naltrexone reversible (512). The presence of preprodynorphin and preproenkephalin in lung carcinoma suggests that kappa and delta receptors might be involved in it (163), but only sigma receptors, with apparently no opiate activity, were found in human renal and colon carcinoma (45). In rats, however, colon cancer was potentiated by Met-enkephalin, and the effect was attenuated by naloxone, so that it may be opiate mediated (218), indicating that different types of cancer have quite different amounts of opiate involvement. Although naloxone alone did not alter colon carcinogenesis in rats (218), chronic naltrexone suppressed growth of mammary tumors that were responsive to estrogen and progesterone but had no effect on those nonresponsive to them (5), suggesting an interaction between the opiates and gonadal hormones might have been responsible for the antitumor activity. The reduction in blood vessel proliferation by morphine and/3-endorphin in chick eggs may have been due to their effect on cell-mediated immunity factors, such as interferons, interleukins, and prostaglandin E2 (392), raising the possibility that the opiates might be useful in the treatment of malignant tumors. In many different kinds of cancer patients, morphine potentiated the suppression of natural killer cell activity, but the opiate increased lymphokine activator killer cells, indicating that morphine given for pain helps one kind of immune function (410). The opiates can modulate malignant growth under a variety of conditions, but the mechanisms involved have yet to be delineated. OTHER BEHAVIORS Among the other behaviors that are mediated, at least in part, by the opiate system is social interaction, both positive and negative. Prosocial behavior was enhanced by deltorphin, since its administration increased the number of social contacts in rats, independent of the stimulation of locomotor behavior (363). MIF- 1 or a synthetic derivative Alatide injected into adult male rats after the first exposure to a juvenile male reduced the time spent in social investigation of juvenile males upon reexposure, although it had no effect on reexposure to a novel juvenile (207), indicating that social recognition can be facilitated by the endogenous antiopiate. Affective defense behavior elicited from the cat by electrical stimulation of the PAG was suppressed by DPDPE and morphiceptin, and this effect was blocked by pretreatment with ICI 174,864 and B-funaltrexamine, respectively (463), suggesting mediation of the response by opiate receptors. Aggression, like defense, appeared to have an opiate base, since naloxone microinjected into the PAG blocked the facilitation or inhibition of the quiet biting attack response in cats after stimulation of the lateral hypothalamus. The action of naloxone was reversed by DAMEA, further supporting the opiate role in predatory attack behavior (558). The opiate system also seems to be involved in behaviors influenced by physiologic rhythms, since the concentration of /~-endorphin changed when rams were exposed to short or long days. Plasma B-endorphin increased the most in response to NMDA in the rats exposed to long days, which produced low amounts of the opiate peptide, and it rose least in those exposed to short days, which produced high amounts of it. Pretreatment with dexamethasone blocked the B-endorphin response, indicating that NMDA stimulates secretion of fl-endorphin from corticotropes, probably acting centrally to produce release of CRF (308). The concentration of fl-endorphin has a circadian

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rhythm that reaches its peak in the morning, but that of Metenkephalin is in an approximate antiphase with it, and their correlations with natural killer cell activity were positive or inverse, respectively (359), indicating that the rhythms of the peptides are important in the modulation of that behavior. The day-night rhythms of nociception and the mu- or kappa-mediated antinociception were reduced by pertussis toxin in the snail, just as in vertebrates. It is likely, therefore, that G-proteins are involved in the cyclical changes of opiate analgesia (578). The metabolism of enkephalin in amacrine cells in the retina, however, it not circadian, but is light entrained, since enkephalin immunoreactive ceils are active in the dark, releasing the peptide faster than it can be synthesized, and are inactive in the light, with a low release rate, so that synthesis outpaces release and builds up a large pool (358). There was also clearly a monthly variation in both Leu- and Met-enkephalin in the ganglia of the periesophaegal ring in Helix aspersa, with peaks in the spring and autumn, when reproduction occurs, suggesting a role in that behavior. There was no definitive regional brain difference for either peptide, though, and Leuenkephalin was higher than Met-enkephalin throughout the year (184). Hibernation is another behavior that may be modulated by the opiate system, since hibernating ground squirrels had higher concentrations of Met-enkephalin in many brain regions, especially in the lateral septal area, than nonhibernating ones. The changes were probably due to seasonal variations rather than body temperature, since they were not found in artificially induced hypothermic squirrels. Hibernation, therefore, might be brought about by an increase in endogenous opiate activity in the brain (376). There still remained some interest in the mechanisms of opiate involvement in electroacupuncture, although the findings did not clarify the picture at all. Naloxone and naltrexone potentiated rather than antagonized it under a wide variety of conditions in rats, including different laboratory methods, geographic locations of the experiments, strains, sexes, weights, and temperature (62,63). It is possible that the technique might activate multiple conflicting neural circuits that interact and ultimately modulate the analgesia (62). The effect was not altered by hypophysectomy or adrenalectomy, so the pituitary and adrenals were not involved, but spinalization or dorsolateral funiculi lesions blocked the analgesia. The inhibition was not affected by IT naltrexone, suggesting supraspinal structures are necessary to produce and potentiate electroacupuncture analgesia (63). The role of the opiate system appears to involve complex relationships. The antitussive properties of the opiates have also been regularly studied. Intracisternal injection of D A M G O or morphine produced a dose-related reduction in cough, with DAMGO having a hundredfold greater action. The effect of both was suppressed by naloxone and DPDPE, although DPDPE had no activity when given alone. The reversal of the action of the two mu agonists by the delta agonist was itself blocked by the delta antagonist naltrindole, suggesting that the opiate antitussive effect is mediated mostly by mu receptors but somewhat by delta ones (233). Chronic morphine produced tolerance to the ability of the drug to soothe cough, but the kappa agonists U-50,488H

and U-62,066E developed no tolerance to it, indicating that the mu receptors were more influential than the kappa ones in this response (232). Opiate receptors on vagal sensory neurons may mediate peripheral opiate-induced antitussive activity, since peripheral-acting BW433C, an enkephalin analog with mu affinity, inhibited the cough reflex. It had previously been thought that the opiates inhibit cough centrally only (9). Naloxone alone did not alter the experimentally induced cough reflex in cats, and the antagonist had no effect on codeine's suppression of it, indicating that the action of codeine was not opiate mediated (372). The possibility of a new opiate assay, electric organ discharge in the electric fish Eigenmannia virescens, was proposed, since morphine lowered the discharge rate in a naloxone-reversible fashion, even though the antagonist had no effect itself (379). It was also reported that a combination of the morphine and naloxone in a single injection produced the same effect as when they were given separately; this would reduce the number of injections to produce the same effect, thus possibly reducing stress associated with the procedure (379). An unrelated finding demonstrated that milk triggers the release of endogenous opiates that bind to kappa receptors. The presence of milk eliminated the wiping response of fetal rats to tactile stimulation of the perioral area, and the milk effect was inhibited by pretreatment with the kappa antagonist nor-binaltorphimine or naloxone, but not by the mu antagonist B-funaltrexamine (475). Interactions of the opiate and CCK systems were found, since potassium-evoked CCK-like material overflow was inhibited by DAMGO or by a low dose of DTLET and was potentiated by a high dose of DTLET or by morphine. The inhibition by DAMGO but not by DTLET was itself suppressed by U50,488H, suggesting that the opiates acting through stimulation of mu, delta, or kappa receptors should increase the net spinal release of CCK. This action might be a mechanism for modulation of pain (47). Other instances of an interaction between the two systems were discussed previously, including CCK's antagonism of/3-endorphin's suppression of maternal behavior (139,140) and of the development of morphine tolerance (252). It also potentiated the inhibition of GI functions by naloxone (200), and its effect was potentiated by naloxone (313). Furthermore, a CCKA antagonist inhibited conditioned place preference with morphine, but a CCKB antagonist potentiated it (205), demonstrating opposite action for different CCK subtypes in their interaction with the opiate system. Dopamine D2 receptor agonists also have affinity for kappa opiate receptors, and it might be that the kappa receptors help regulate dopamine release (148). Numerous other interrelationships between the dopamine and opiate systems have previously been discussed in this review and need no further review, except to note their complexity. If there is eventually to be a delineation of the physiological roles the opiate system have in the many behaviors reported here, interactions such as these should be of value when studied by a systematic, paradigmatic approach. ACKNOWLEDGEMENTS This work was sponsored in part by the VA. Thanks are given to Shay Clark for her help with the preparation of this manuscript.

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