Endogenous opiates: 1987

Peptides,

Vol. 10, pp. 205-236. © Pergamon Press plc, 1989. Printed in the U.S.A.

0196-9781/89 $3.00 + .00

REVIEW

Endogenous Opiates: 1987 G A Y L E A. O L S O N , * R I C H A R D D. O L S O N A N D A B B A J. K A S T I N * ~

Department of Psychology, University of New Orleans, New Orleans, LA 70148 and *Veterans Administration Medical Center, New Orleans, LA 70146 and ~fTulane University School of Medicine, New Orleans, LA Received 18 A u g u s t 1988 OLSON, G. A., R. D. OLSON AND A. J. KAST1N.Endogenous opiates: 1987. PEPTIDES 10(1) 205-236, 1989.-This paper is the tenth installment of our annual review of the research during the past year involving the endogenous opiate system. It covers the nonanalgesia and behavioral studies of the opiate peptides published in 1987. The specific topics this year include stress; tolerance and dependence; eating; drinking; gastrointestinal and renal activity; learning, memory, and reward; cardiovascular responses; respiration and thermoregulation; seizures and other neurological disorders; electrical activity; locomotor activity; sex, pregnancy, and development; immunology and cancer; and other behavior. Stress Tolerance Dependence Eating Drinking Alcohol Depression Learning Memory Cardiovascular responses Temperature Respiration Epilepsy Activity Aging Aggression Mental illness Sex Immune system Opiate Peptide

IN 1987, as in previous years, the amount of research dealing with the endogenous opiate system continued to grow, and we are beginning to develop a better understanding of the behaviors controlled or modulated by the opiates and the mechanisms underlying them. There is still, unfortunately, much that remains unclear about the physiologic actions of the opiate peptides, but we are gaining some information about them. It seems that many behaviors that have not typically been seen as opiate in nature are influenced by the opiate system, so that more needs to be studied to understand their functions. In some areas of research we are getting a grasp of the role of the opiates, but in others the findings are so contradictory as to not allow any generalizations, much less definitive answers. This paper is the tenth installment of our annual series of reviews and deals with behavioral and nonanalgesic studies during 1987. Although traditional analgesic studies are not covered, those of stress-induced analgesia are. Stress-related phenomena, including analgesia, continued to be of considerable interest in 1987, perhaps because of the widespread obsession with reducing stress in our daily lives. Although the opiate system clearly seems to be involved in mediating responses to many kinds of stress, the underlying mechanisms are not so easily determined. The current interest in the drug problem in society has prompted investigators to search more for the causes and results of opiate addiction, as well as possible improvement in treatment. Similarly, the prevalent emphasis on eating disorders and obesity has stimulated research in the opiate mediation of eating in general. The control of drinking, too, especially consumption of alcohol, is a source of particular medical interest, and the opiate system appears to be more involved in it than was thought earlier. Research on the role of the opiates in gastrointestinal activity and bladder control has also grown in recent years.

Although there used to be much interest in the mediation of emotional and mental disturbances by the opiate system, such interest has greatly dwindled in recent years, and little success has come from studies of it. Work shifted in 1987 from investigating opiate involvement in schizophrenic responses to its possible role in depression. Perhaps the area of biggest growth of research in 1987 was in the area of memory and learning, and the mediation of reward by the opiate peptides. Although we are still far from understanding what the opiates might do in these processes, significant effort has been expended in attempts to find out. There is still great interest in the opiate mechanisms of cardiovascular responding, although it, like learning, has not yet yielded as much information as desired. Conversely, there has been a decline in the amount of work being done to determine the role of the opiate system in respiration and thermoregulation in recent years. Interest remained high in the possible opiate mediation of seizure activity and the possible treatment of spinal cord injury with opiate antagonists. With the increasing attention given to research on Alzheimer's disease, the role of the opiate system in it was studied more in 1987. Areas that have always received much attention are electrical and locomotor activity, and this continued to be true in 1987, with particular interest in the mediation of the effect of exercise by the opiates. Another area of increasing interest is opiate modulation of sexual activity, pregnancy, and development, especially aging. Finally, the relationship of the opiate peptides to immune reactions and cancer, as well as other behaviors, such as fighting and hibernation, is reviewed in this paper. STRESS

The endogenous opiate system has long been implicated in many of the effects of stress, both the behavioral and physio-

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206 logical responses to stress. Stress has been shown to cause release of opiate peptides, which may mediate these reactions, although not all responses to stress are opiate in nature. Whether or not the opiate peptides play a role in any particular stress-induced behavior depends on the kind of stress and the variables studied. One of the most frequently studied stressors in the past was electric footshock in animals, which produces a variety of effects, including analgesia. Although shock reliably produces antinociception, it is sometimes opiate mediated and sometimes not, depending on the specific parameters used. In 1987 there was less interest in those experimental manipulations than previously, although some work was done in this area. Inescapable and unsignalled shock presented intermittently resulted in analgesia that was naloxone reversible (400) or blocked by naloxone (173), suggesting its opiate nature. Lack of control over the shock seemed particularly important, since rats given escapable shock did not demonstrate decreased perception of pain (173). The ability of Tyr-MIF-1, an endogenous opiate antagonist, to block the effects of shock-induced analgesia depended on the intensity of the shock, with antagonism occurring at moderate but not at high levels, indicating that an endogenous antiopiate system can discriminate levels of stress (130). Footshock has been shown to produce other opiatemediated effects also, such as alteration in activity level. After mild, inescapable shock, freezing occurred initially, followed by a period of increasing activity that exceeded that for the noshock group. Morphine (5.0 but not 0.5 mg/kg) attenuated the freezing and potentiated the hyperactivity of the shocked rats (258). Ultrasonic distress calls elicited by shock in rats were suppressed by B-endorphin, an effect that was blocked by naloxone (408), indicating a role for the opiate system in this response. An elevation of blood pressure induced by shock was reversed by opiate antagonists (111), suggesting that the opiate peptides might be involved. The hyperthermia produced by shock was partially mediated by the endogenous opiates. Although neither naltrexone nor morphine affected the peak rise in temperature, they both slowed the return to baseline (328). Shock also disrupted the accuracy and slowed performance of rats in a discrimination task, but in this case the effect was apparently not opiate in nature, since naltrexone did not alter it (151). Footshock has been shown to selectively influence particular pools of opiate peptides. Repeated shocks over days increased immunoreactive dynorphin, c~-neo-endorphin, and Met-enkephalin in some areas of the spinal cord but not others. There was no alteration of/3-endorphin, dynorphin, or Met-enkephalin in brain tissues, although there was an increase of ~3-endorphin in the pituitary (348). Acute footshock enhanced the release of/3endorphin and N-acetylated f3-endorphin from the pituitary, and prior treatment with amphetamine enhanced this release, suggesting a change in opiate-mediated responses to stress after sensitization with amphetamine (361). Another form of stress, restraint, also produced analgesia (218, 222, 225, 230, 245). Naltrexone blocked but could not reverse the stress-induced antinociception after prolonged restraint, and a quaternary form of the antagonist had no effect when administered systemically, indicating a central nervous system (CNS) effect (225). Restraint-induced analgesia was also blocked by naloxone in mice (218) and deer mice (222), although in deer mice the level of analgesia varied with sex, with males displaying greater amounts, and with population, with insular deer mice having more analgesia than mainland ones. Calcium channel antagonists enhanced and their agonists

OLSON, OLSON AND KASTIN attenuated the antinociceptive effects of restraint (218), suggesting an interaction of calcium channels and the opiate system in this response. Repeated restraint for eight days in pregnant rats altered the pain threshold in the pups at maturity. The prenatally stressed females had a lower pain threshold than control females, but there was no effect in males. The response to morphine-induced analgesia was also affected, with prenatally stressed females having greater analgesia and males less analgesia than controls (230), thus suggesting that the early stress altered the development of the opiate system. A single acute stress modified rats' responses to morphine 24 hours later, decreasing the sensitivity to morphine unless an opiate antagonist was given immediately after stress, producing increased sensitivity to morphine in the tail flick test. Opiate binding was altered by the stress and the antagonist, accounting for the finding (2,3). The duration of immobilization affected the opiate involvement in the analgesia, since after 30-min restraint, naloxone partially reversed the analgesia, and there were changes in Metenkephalin-like immunoreactivity in parts of the brain, but after 180 min of stress, no change in any brain area tested was noted (245). An increase in plasma Met-enkephalin was also noted after restraint (27,333), with the effect being modulated by adrenal demedullation and chemical sympathectomy (27), indicating sympathetic mediation of the opiate response to stress. Plasma j3-endorphin rose in response to restraint, with systemic administration of histamine antagonists inhibiting that response (15), suggesting more complex interactions of the opiate and other systems after stress. Restraint affected locomotion as well as pain perception. Immobilization increased locomotor activity in mice, and that effect was modulated by the calcium system, with calcium channel antagonists enhancing it and agonists blocking it (218). In deer mice, population location influenced the locomotor response to restraint, as it did for analgesia, with an increase in activity level for mainland animals and a decrease for insular ones. In addition, males had greater changes in activity than did females after restraint, indicating marked differences in the endogenous opiate system even within species (222). Cardiovascular activity is another response modified by restraint. There are initial increases in blood pressure and heart rate after restraint that are modulated by naloxone or naltrexone. Small doses of naloxone potentiated the tachycardia and attenuated the pressor response, while larger doses of it and chronic administration of a larger dose of naltrexone attenuated both (284). After prolonged immobilization, blood pressure falls, presumably due to a release of opiate peptides. Naloxone pretreatment prevented the drop, and adrenalectomy attenuated it, suggesting that opiates from the adrenals are partially but not exclusively involved in this response (318). Blood pressure is also affected by another form of stress, cold ambient temperature, which produced a naloxone-reversible elevation of blood pressure in rats (111), indicating opiate involvement in this response. Cold, however, induced analgesia in snails that was unaffected by naloxone (116,117), a delta receptor antagonist (116), and by the endogenous antagonists MIF-1 and Tyr-MIF-I (117), suggesting that the opiate system does not mediate the analgesia. Warm temperatures, though, produced antinociception that was blocked by those antagonists (116,117) and by a mu receptor antagonist (116). Supporting the notion that heat-stress effects are mediated by the opiate system is the increase in plasma B-endorphin immunoreactivity found in cancer patients undergoing whole body hyperthermia (360). Forced swimming is another stressor that results in analge-

OPIATES: 1987 sia, but the amount of opiate involvement depends on the specific conditions being studied. Warm swims typically produced analgesia that could be antagonized by naloxone (223,444) or Tyr-MIF-1 (130), although the effect was sex specific, since it was not reversible in males (444). Analgesia was weaker in female than in male rats, but females had more hypothermia than males after cold and warm water swims. Intact males and females had greater analgesia and hypothermia than gonadectomized ones after both cold and warm swims, but the reverse was true for activity level, with gonadectomized rats showing increased activity after warm water swims (367). The duration of the swim also determined its ability to be blocked by some opiate antagonists, since only those at moderate times produced reversible analgesia (130). Analgesia from forced swims at room temperature was not naloxone reversible (400) and was enhanced by prenatal treatment with ethanol in male but not female rats (20). In rats that had received naltrexone implants for eight days, morphine potentiated the analgesia induced by cold swims in those with the pellet removed and blocked it with the pellet intact (450), indicating the opiate nature of the response. Involvement of the opiate system in aggression-induced analgesia was also studied in 1987, with the parameters being investigated being the determining factors. It was nonopiate in the early phase of fighting (365,385) but opiate with extended conspecific attack (365). Preexposure to a nonaggressive mouse opponent prevented the development of analgesia, and naloxone abolished the preexposure effect (385), indicating a role for the opiate peptides in the response. Calcium channel antagonists facilitated and agonists inhibited the defeat-induced analgesia displayed by intruders, suggesting the calcium channel might modify endogenous opiate activity (215). The stress associated with surgery and other medical procedures has been shown to activate the opiate system in some cases. Surgery in lambs typically done without anesthesia, such as tail docking (384), removal of impacted molars (165), and second-trimester abortion by prostaglandin (132), increased immunoreactive ~-endorphin in the plasma, although there was no change in its concentration in patients undergoing surgery with general or spinal anesthetic (341). It is possible that an early elevation was missed due to procedures used, however, since no measure was taken until 30 min after the beginning of surgery, but it is unlikely that the peptide played a role in postoperative analgesia, with no change being observed up to 90 min after its beginning. The circadian rhythm of ~-endorphin could be altered in baboons, with the duration of the disturbance depending on the severity of the trauma. For the high trauma group, the alteration lasted more than one week (273). The endogenous opiate system, thus, appears to play a role in the management of pain during these procedures. A novel environment can be stressful enough to produce analgesia which is reversible by naltrexone (386) or Tyr-MIF-1 with mild pain only (130). Familiarization with the situation before testing eliminates the analgesia (386), as does repeated testing, but the habituation to the apparatus was blocked by naloxone (364), indicating an opiate component to the response. Psychological stress from hearing and seeing others shocked induces a weak analgesia that is cross-tolerant with morphine and which shows tolerance with daily exposure, suggesting mediation by the endogenous opiates (400). Short-term but not long-term isolation and intense light and sound raised blood pressure, and the effect was naloxone or naltrexone reversible (111), indicating that the opiate system might be involved in the reaction to these stresses. Body rotation is another stress that produces opiate anti-

207 nociception. Naloxone blocked the analgesia in snails (404) and deer mice (193), suggesting its opiate nature. Greater analgesia resulted from intermittent than from continuous rotation, and there were population differences among deer mice, with insular animals having a stronger effect than the mainland ones. It was suggested that the finding might have implications for an evolutionary basis of motion sickness (193). Exposure to magnetic fields reduced the analgesia induced by morphine (324) and by warm water swims (223). Magnetic stimuli also eliminated the day-night rhythm of stress-induced analgesia, suggesting a possible interaction between the pineal and the opiate system (223). Concentrations of/3-endorphin in plasma rose after mild stress such as handling or administration of ether in rats (198) or submersion in a state of neutral buoyancy in scuba divers (4). There was also a marked elevation of enkephalin mRNA in the hypothalamus after naioxone-precipitated opiate withdrawal or after intraperitoneal (IP) injection of hypertonic saline in rats (262), indicating an activation of the opiate peptides with stress. Similarly, adjuvant-induced inflammation of the paw in rats produced an increase in dynorphin in the spinal cord and a supersensitivity to morphine (390). Analgesia resulting from 24-hour food deprivation was observed in rats. Prenatal pretreatment with ethanol enhanced the effect in males but not females (20), suggesting an alteration of the development of the opiate system in those males. A developmental trend was also noted in the involvement of the endogenous opiates in reaction to stress from injections, since naloxone blocked the response in adults but not in neonatal rats (17). The coulometric hypothesis proposes that with (intensity x duration) of an aversive event, small products induce opiate hypoalgesia and large products induce nonopiate hypoaigesia. Since increasing the duration attenuated nonopiate hypoalgesia, and since mild shocks that have the same product do not produce equivalent hypoalgesia, Grau (148) proposed an alternative "working memory" hypothesis to account for the findings. He suggested that a representation of an aversive event in working memory resulted in the hypoalgesia and that displacing the representation by following the intense shock by a weak one as a distractor should attenuate the hypoalgesia, and it did. This new hypothesis might account for some of the discrepant data not explained by the coulometric one. TOLERANCE AND DEPENDENCE A classic characteristic of the opiates, both exogenous and endogenous, is their development of tolerance and dependence. It has long been of interest to study the variables that affect this property and to attempt to understand the mechanisms of it. One question of interest to investigators in 1987 was how tolerance develops, and another was what affects withdrawal symptoms once tolerance has occurred. These topics and a few others are discussed in this section. It appears that chronic use of exogenous opiates alters the endogenous opiate system to some extent, a proposed mechanism to account for tolerance. Chronic administration of heroin in rats raised the concentrations of dynorphin B and [MetS]enkephalin-Arg6-Gly7-Leus (ME-RGL) in discrete areas of the brain. Specifically ME-RGL increased by 50°7o in the substantia nigra, and dynorphin B increased 188% in the globus pallidus and 42o7o in the ventral tegmental area (436). Morphine, administered for five consecutive days in increasing doses, decreased preproenkephalin and preprodynorphin mRNAs in the striatum to 30-40°7o and they remained below normal during

208 withdrawal. Treatment with naloxone or naltrexone increased both to 200% of baseline (369). Chronic morphine, however, had no effect on total 13-endorphin immunoreactivity in the brain, although the investigators did not exclude the possibility that it did change the rate of POMC processing and t3-endorphin 1-31 turnover (46). Patients on methadone maintenance for 10 months had elevated concentrations of t3-endorphin in the cerebrospinal fluid (CSF) but not in plasma (239), indicating that the site of measurement is critical. The specific receptors involved in tolerance have also been studied. Daily injections with morphine or [D-AlaZ-MePhe4, Gly(O1) 5] enkephalin (DAGO), both mu agonists, or a delta agonist, D-AlaZ-D-LeuS-enkephalin (DADLE) had similar time courses for the development of tolerance, suggesting a common mechanism for it. Since there was no cross-tolerance between them, however, it was thought to be a common but independent mechanism (393). The development of different aspects of tolerance to morphine varied, however, according to the kind of receptor involved. Tolerance to analgesic effects, associated with the mul receptor, occurred early, but there was no tolerance to morphine's respiratory depressant actions, mu2 effects. Likewise, tolerance to release of prolactin (mul function) developed but not to release of growth hormone (mu2 function) (263). Tolerance to/3-endorphin is probably a result of epsilon receptors, since there was no cross-tolerance with mu or delta agonists in rats dependent on 13-endorphin (201). The development of tolerance also depends on the degree of initial drug effect, which is primarily dependent on dose, and time of receptor occupancy, which must be longer than the time to reach the peak response to the drug (182). An interaction was noted between the opiate and dopamine systems with respect to tolerance, since lithium used to block the development of supersensitive dopamine receptors in response to acute administration of opiates enhanced the development of tolerance to morphine (285). Short-term intermittent blockade of the opiate receptors was sufficient to attenuate development of dependence on methadone, since naloxone given every other day during daily methadone maintenance for two weeks reduced naloxone-precipitated withdrawal symptoms on the fifteenth day (243). Similarly, pretreatment with the endogenous antagonist MIF-1, either once for short-term opiate exposure or daily for long-term opiate administration, interfered with the development of tolerance to morphine (277). Tolerance can develop rapidly, even with one dose of morphine. Withdrawal symptoms were shown when naloxone was administered two hours after a single injection of morphine in guinea pigs, and naloxone reversed the inhibition of the guinea pig ileum induced by a single application of morphine (62). In another in vitro preparation, chronic exposure to morphine of pituitary tumor cells, which contained a homogeneous population of mu receptors, produced tolerance within five hours, with cross-tolerance to DADLE (349), suggesting this was a useful model in the study of tolerance. Likewise, chronic exposure of cultures of fetal mouse spinal cord explant to opiates attenuated the depression of the cells by acute opiates. It also inhibited the response to serotonin, suggesting a possible crosstolerance to serotonin (350). Another model to study tolerance, this one in vivo, involved self-administration of the opiates by volitional drinking. Rats were given a choice between the drug and vehicle, with the positions of the bottle being rotated to eliminate position preference and the bitter taste of the opiate being eliminated with fentanyl citrate. The model thus overcame problems with previous ones (57). A refinement of methodology of measuring tolerance to thermal effects of opiates

OLSON, OLSON AND KAST1N involved testing over a number of intervals rather than at a single one and thereby possibly missing effects. In doing so, tolerance to both hypo- and hyperthermia induced by morphine was reported, as opposed to previous findings of tolerance only to the hypothermic effect (305). Great interest was displayed in 1987 in the variables that affect the severity of symptoms of naloxone-precipitated withdrawal in opiate-dependent rats. Factors associated with the immune system, including interferon (78, 93,251), muramyl dipeptide (66,92), gamma irradiation (91), cyclosporin A (174), cortisol, and cyclophosphamide (297), reliably attenuated the symptoms, suggesting an interaction between the immune and opiate systems. Inhibitors of enkephalinase, phelorphan (159) and thiorphan (158), which increase the level of enkephalin, also attenuated the signs of naloxone-precipitated withdrawal. Likewise, ketamine alleviated the symptoms of withdrawal as well as developing tolerance itself and showing cross-tolerance with morphine (108). Withdrawal from morphine in mice produced a variety of responses, including explosive motor behavior, increased grooming, decreased body temperature, disrupted walking and rearing, and more attack bites and threats toward an intruder. Dopamine receptor agonists suppressed the motor and aggressive responses (293). As indicated above, if naloxone is given regularly during the development of tolerance, withdrawal symptoms associated with acute administration of naloxone are less severe, although mild withdrawal occurred with each challenge by naloxone during development of tolerance. There was no change in intensity of the symptoms over the seven challenges, however. Overall, there was a weakening of the tolerance as a result of the procedure (243). If morphine-dependent rats were given methadone (a mu agonist) or pentazocine (a kappa agonist) and then abstinence for two weeks, subsequent opportunity to self-administer morphine resulted in protracted abstinence signs that differed in kind and severity depending on receptors involved. Maintenance with the kappa agonist produced less severe symptoms than mu maintenance (451). Similarly, withdrawal from morphine and U-50,488 or Mr 2033 (both kappa agonists) differed, but the two kappa agonists had similar signs. There was, however, cross-tolerance from Mr 2033 to morphine but not the other way, since withdrawal from the former was suppressed by the latter (140). Withdrawal from mu agonists in the rhesus monkey involved apprehension/aggression, coughing, retching, vomiting, and miosis, but withdrawal from kappa agonists produced general hyperactivity, unusual tongue movements, yawning, scratching, grooming, and picking of fingers and toes, thus demonstrating significantly different patterns of withdrawal for the agonists (445). Different withdrawal symptoms were also reported for morphine-dependent rats given naltrexone subcutaneously (SC) or methylnaltrexone intracerebroventricularly (ICV), although both displayed aversion to the place of withdrawal. There was no relationship between the individual withdrawal signs and the aversive effect (304). Naloxone (SC) and methylnaloxonium (ICV), however, produced similar suppression of operant responding in morphine-dependent rats. Injection of methylnaloxonium into the periaqueductal gray or dorsal thalamus had similar results to the ICV administration, but injection into the nucleus accumbens had a stronger effect, suggesting that receptors in the nucleus accumbens may be responsible for the reinforcing properties of the opiates and for the compensatory changes associated with withdrawal (237). Cerebral noradrenergic neurons were linked to the physical signs of withdrawal, and dopaminergic and serotonergic neurons were important to

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the mediation of the reinforcement and reward of morphine, since their functioning was differentially altered during withdrawal from morphine (6). Morphine-dependent rats were tested for signs of abstinence the day after their pumps were removed under conditions of transcranial auricular electrostimulation (TCET). The TCET rats had fewer signs, and the effect was naloxone reversible, suggesting that TCET might be helpful in the management of opiate abstinence syndrome (307). The CSF taken from dependent rats after six hours of abstinence was injected IP or infused into the third ventricle of dependent rats, precipitating abstinence signs that were similar to those of naloxone, suggesting that dependent animals may secrete an endogenous antagonistic substance (280,281). In rats with spinal tolerance to morphine due to chronic infusion intrathecally (IT), naloxone precipitated mild withdrawal symptoms, and subsequent 1P injection produced analgesia, indicating that the spinal tolerance did not spread to other areas (269). Tail skin temperature was monitored after central administration of naloxone in morphine-dependent rats. Regardless of site of injection, into the locus coeruleus, preoptic area-anterior hypothalamus, or frontal cortex, the temperature increased, indicating that morphine dependency sensitizes several brain regions to naloxone (214). Clonidine blocked and phentolamine decreased the temperature surge, indicating that noradrenergic neurons play a role in the response (213). Rectal temperature decreases under the same conditions, so that there is a dissociation of tail skin and rectal temperature responses to opiates (213). Dissociation of other properties of morphine was seen in a case history of a cancer patient receiving morphine and pethidine for pain, for which he developed tolerance. The tolerance for the pain did not protect him, however, from a moderate degree of respiratory depression (242). In another case history, a patient who had developed tolerance to the analgesic properties of morphine was given methadone. The pain was relieved, but the patient became agitated, disoriented and unresponsive, and had hallucinations, all indicating withdrawal. Reintroduction of morphine alleviated the psychological symptoms, but the pain returned, thus indicating a dissociation of those responses to opiates (65). EATING

Interest in attempting to delineate the role of the endogenous opiate system in the control of eating has increased over the past several years, and 1987 was no exception. There seems little doubt that the opiate agonists and antagonists can modulate consumption of food, and the major focus of research in this area is the nature of their probable physiological involvement. In general, the agonists have been found to stimulate eating, and the antagonists inhibit it, although many variables such as the specific agent, site of administration, and species have been shown to alter those effects. Agonists specific to several different receptors seem to be effective in manipulating food intake, although those associated with the kappa receptor have drawn the most attention since they appear to be among the most important for this response (298). Kappa agonists have reliably increased eating (101, 144, 145, 162, 178,219, 220, 221,235,298, 392), as have mu agonists (102, 144, 145, 162, 211,220, 221,257). Delta agonists are less consistent in stimulating eating, sometimes producing the effect (145) and other times not (144), depending in part on site of administration. Although not much has been done with them, epsilon agonists also appear to be important here (298).

The mu agonist DAGO increased eating when microinjected into the amygdala, but dynorphin A (a kappa agonist) and DSLET ([D-Ser2,LeuS]enkephalin-Thr 6, a delta agonist) had no effect, although both DAGO and dynorphin A facilitated intake when administered into the hypothalamus (144). All three peptides given ICV stimulated eating (145). Both dynorphin and morphine increased eating if injected into the nucleus accumbens or the ventral tegmental area, but in the paraventricular nucleus, only dynorphin had a weak facilitory effect, and neither influenced eating in the periaqueductal gray or substantia nigra-pars reticularis (162). Specific brain areas, thus, are critical to the effect. Lesion studies support the notion that the paraventricular nucleus, ventromedial hypothalamus, and dorsomedial hypothalamus are important areas (143). Enkephalinase inhibitors reacted differentially, depending on route of administration. When given orally, acetorphan but not thiorphan produced a biphasic increase in eating, but when administered ICV thiorphan but not acetorphan inhibited intake, and when injected intravenously (IV), thiorphan stimulated eating, and acetorphan produced an early decrease followed by a later increase for an overall no effect (358). A novel oxime derivative of naltrexone (NPC 836) stimulated food intake and acted like an agonist in vitro, binding to mu, delta, and kappa receptors (235). Biphasic effects were noted in several studies, suggesting that the timing of the studies after administration of the opiates is critical and that differences in findings might be due to this variable. The kappa agonists U-50,488 and PD 117302 initially stimulated eating, but then inhibited it from 6-24 hours after administration, producing an overall 24-hour decrease in consumption at small doses, and larger doses of PD 117302 had no early effect but lowered intake over 24 hours (178). In fooddeprived rats, morphine increased feeding during the first two hours, but the effect diminished during the next two hours after IP injection and by the sixth hour after administration into the lateral hypothalamus. Since the agonist produced no effect in nondeprived rats, deprivation clearly is another variable that needs to be taken into account (211). There are species differences in the involvement of the endogenous opiate system in eating. Rats and mice respond differently to morphine, and monkeys and humans respond differently to naltrexone (14). Dynorphin produced the opposite effect in two-day-old chicks that it typically does in other species, inhibiting eating at some doses and having no effect at others (392). Morphine had no effect on eating in wild deer mice, although U-50,488 increased consumption (221). The American cockroach, however, responded to U-50,488 in a manner similar to other species, with increased intake (219). As with other animals studied, molluscs and arthropods seem to have a dissociation of the components of natural feeding behavior, with mu agonists mediating foraging and kappa agonists mediating ingestion (220). Along the same lines, opiates appear to have a role in the maintenance and not the initiation of eating (298). The 1 but not the d enantiomer of the kappa agonist U50,488 increased consumption of highly palatable food in nondeprived rats, and the effect was naloxone reversible (101). Morphine also produced a naloxone-reversible stimulation of intake of sweetened chow and sugar, but apparently morphineinduced feeding seems to require integrity of the dopaminergic system as well, since a dopamine antagonist also inhibited the effect (102). Destruction of the norepinephrine nerve terminals by 6-OHDA did not alter the opiate-increased eating or its preferential stimulation of fat and protein intake in rats (396).

210 Another condition that was reported to influence opiatemediated eating was diabetes, with administration of DAGO into the right ventricle having no effect in normal rats but facilitating the increase in diabetic ones (257). Just as opiate agonists regularly increase eating, opiate antagonists alone reliably decrease it (68, 76, 102, 141, 219, 232, 389, 394, 396, 429, 449) with few exceptions. In two-dayold chicks naloxone increased intake (392), suggesting a developmental or species effect for opiate-mediated eating. Naloxone and naltrexone suppressed eating in adult broiler and leghorn chickens (272), indicating that the previous effect was a developmental one. Naloxone inhibited consumption in the spiny mouse (76), American cockroach (219), and rats (232), but in the spiny mouse the latency to respond to food was not affected (76), whereas the interval between meals was increased in rats. In rats the duration of meals was decreased, but meal frequency and eating rate were unaffected by naloxone or naltrexone (232). Another exception to the generalization that antagonists suppress eating was reported for a low dose of naloxone (0.125 mg/kg) which had no effect in rats, although it did reverse the stimulation of food intake by growth hormone releasing factor (GRF), suggesting an interaction between the opiate system and GRF (418). Vasopressin might also interact with the opiates in the control of eating, since naloxone suppressed food consumption in Brattleboro rats (homozygous for diabetes insipidus and lacking the ability to synthesize vasopressin) more than it did in normal rats (449). Sex hormones might also interact with the opiate system for this response, since the effect of naloxone in female rats depended on the estrous cycle, although in males there was no effect for variations in testosterone (429). Adrenalectomy, however, had no effect on the anorexia induced by naltrexone or diprenorphine (68), indicating that adrenal opiates were not involved in this response. Long-term inhibition of intake and concomitant weight loss in rats were reported after administration of fl-chlornaltrexamine, a nonequilibrium antagonist which alkylates and inactivates opiate receptors (145). Although antibodies to t3-endorphin had no effect on eating, antibodies to dynorphin A inhibited electrically-elicited feeding in rats in a manner similar to that found for naloxone, suggesting to the investigators that dynorphin was involved in the control of ingestive behavior and that the anorectic action of naloxone may result from antagonism of dynorphinergic transmission (58,59). Since antagonists tend to suppress eating, it seems logical that they might be useful in the treatment of eating disorders. Limited support for that notion has been found, however. In bulimics, all of whom were engaging in binging and purging daily, large doses (200-300 mg daily) of naltrexone significantly decreased both binging and purging, although smaller doses (50-100 mg daily) had no effect (141). Increasing doses of naltrexone (25-200 mg) over four consecutive days decreased intake of laboratory luncheon meals by 30% in obese men, and meal size remained suppressed during the week after administration. Rates of ingestion and subjective ratings suggested that naltrexone decreased appetite rather than promoting satiety. Body weight, however, was unaffected (389), indicating that the value of naltrexone therapy for obesity is questionable. Similarly, although naltrexone reduced intake of carbohydrates, it increased consumption of fats, so that there was little weight loss (396). There does, however, appear to be a disturbance of the endogenous opiate system in at least some forms of eating disorders. Obese subjects had higher concentrations of plasma

OLSON, OLSON AND KASTIN fl-endorphin in plasma and CSF than lean subjects (14). Clonidine produced elevated concentrations of serum fl-endorphin in obese but not normal women, and although naioxone did not affect t3-endorphin, the antagonist impaired the growth hormone response in obese women, suggesting that hypothalamo-pituitary dysfunction in obesity might he related to abnormalities in the opiate system (23). Not all hypothalamic dysfunction present in obesity can be accounted for by an altered opiate system, however, since the prolactin response to DAMME (D-Ala2-MePhe4 Metenkephalin-(u)-ol or FK33-824) was the same in obese and normal women. Obese women, however, did show impaired growth hormone release after both DAMME and insulin-induced hypoglycemia compared with lean women (109). Fat Zucker rats had increased dynorphin in the cortex and midbrain compared with lean Zucker rats on a normal diet, suggesting a hereditary component to the opiate disturbances in obesity, although diet also played a role (416). Food deprivation changed the amount of immunoreactive dynorphin A (1-8) found in discrete brain regions of lean and fat Zucker rats. Deprivation increased dynorphin in the cortex in both lean and fat ones, increased dynorphin in the hippocampus in fat ones, decreased it in the striatum in lean ones, and decreased it in the midbrain in fat ones (416). The effects of fasting on Met-enkephalin in the hypothalamus depended in part on circadian rhythms, since the peptide increased in the paraventricular nucleus and the ventromedial hypothalamus only in the dark-fasted rats (276). Fasting also produced higher concentrations of Met-enkephalin in the basomedial hypothalamus, amygdala, and olfactory bulb in sheep (16). A decrease in the number of binding sites for 3H-naloxone in the hypothalamus and medulla oblongata was also found in rats (30). After eating, the concentration of fl-endorphin fell in the dorsomedial and posterior hypothalamus in sheep (16). The specific type of diet eaten was not as important. Rats given isocaloric diets differing in percent of protein (4-50°7o) for four weeks had no differential distribution of morphine in the brain or blood and no differential binding in the mu, delta, or kappa receptors (37). In mice fed diets with either 25070 butter fat or 25°7o corn oil, receptor binding was not affected in C3H mice, although in C57BL/6 mice corn oil produced greater binding affinity. Both types of rat gained weight on the fat diets, relative to controls given typical rat chow, but the effects of fat in diet on body composition and receptor binding were unrelated (250). Besides its involvement in obesity, the role of the opiate system in anorexia nervosa has been studied. Anorexics had lower concentrations of immunoreactive fl-endorphin in the CSF than did normais. After six weeks of treatment, with accompanying weight gain, these patients had concentrations similar to controls, and after a year of weight restoration, they maintained the normal concentrations (224). An indirect measure of t3-endorphin concentrations in anorexics involved an exaggerated mydriatic response to naloxone applied to the eye in anorexics as opposed to normals, indicating a possible diagnostic confirmatory tool and one helpful in evaluating changes in the peptide during the course of the disease (150). The atypical opiate system of the BALB/C mouse may resemble that in anorexic patients, thus providing an animal model for the disease. In this mouse, morphine decreases food intake and blood glucose and increases motor activity, which is opposite of normal (283). This finding suggests an autoaddiction model of the disease, with the initial period of dieting inducing release of the endogenous opiates, which produces positive reinforcement (elation) and a self-perpetuating addic-

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tion to eating (270,283). Support for this model comes from the fact that the clinical picture of anorexia resembles an addictive disorder, the fact that the CSF of anorexics has elevated endogenous activity, and the fact that opiates are released during food restriction (270). The endogenous opiate system may play a dual role in starvation, including increasing food intake and down regulating functions to an absolute minimum. An uncoupling of these functions can produce an eating disorder, and anorexia might involve the second function without the first (270,283). Antagonists, since they interrupt the addictive cycle, may be helpful in treatment (283). DRINKING The possible mediation of the consumption of fluid, like that of food, by endogenous opiates has been studied in the past, but in recent years, less research has been done, perhaps because results from drinking studies have been less consistent or perhaps because the commercial potential may be smaller. The control of drinking is more complex than that for eating, and the experimental parameters appear to be more critical for the former, thus preventing general conclusions about the role of the opiate system here. A large portion of the work in this area in 1987 centered an opiate modulation and regulation of alcohol intake. Reports of the effects of morphine were inconsistent, although the experimental conditions were similar. In one case (183), morphine increased intake of a sucrose solution in a twochoice paradigm, but another study (271) found that the same dose of the opiate inhibited sucrose intake relative to water intake when given a choice. Strain differences and the presence or absence of deprivation of water were possible variables accounting for the discrepancies. Both studies used repeated testing over days, and one reported that the altered consumption of sucrose was maintained even days after withdrawal from the morphine (271). Neither morphine nor dynorphin, when microinjected into the ventral tegmental area, paraventricular nucleus, periaqueductal gray, nucleus accumbens, or substantia nigra-pars recticulata, had any effect on drinking (162). Interestingly, ingestion of saccharin for 21 days produced cross-tolerance for morphine (1), suggesting that chronic consumption of the highly palatable substance might have altered the endogenous opiate system, perhaps by a reward mechanism. The dose of the kappa agonist U-50,488 was critical, since 1.0 mg/kg inhibited intake of sucrose, but 0.1 mg/kg stimulated it (271). The effect of the peptide apparently is stereospecific, since ICV administration of 25 or 100 nmol of the 1 but not the d enantiomer of U-50,488 decreased consumption of water in deprived rats (101). Another kappa agonist, PD 117302 at 5 mg/kg, however, had no effect on drinking of water at all (178). The effects of opiate antagonists on drinking were more consistent, since they generally suppressed the behavior. Intake of both water and a highly-palatable saccharin-glucose solution was inhibited by naltrexone in both deprived and nondeprived rats, although water deprivation enhanced the effect (231). Both naltrexone and naloxone reduced drinking in broiler and leghorn chickens for 300 min, but consumption over 24 hours was not affected (272). In the spiny mouse, intake of water was lowered after naloxone, but the latency to drink was not altered (76), suggesting opiate control of satiety here. The antagonist also retarded the acquisition of schedule-induced polydipsia in rats but did not affect drinking after training was completed (357).

Quaternary forms of antagonists administered centrally suppressed drinking (52,417), except naltrexone into the lateral hypothalamus (417), but the tertiary form of naltrexone had no effect when injected anywhere centrally, possibly because of its rapid diffusion into the surrounding brain tissues (417). Naloxone lowered the amount of water consumed in both Brattleboro and normal rats, but the effect was greater for normal ones, suggesting that the opiate system might interact with vasopressin in the control of drinking (449). One negative finding concerning the antagonists involved the lack of an effect for increasing doses of naltrexone over four consecutive days on drinking in obese men (389). As indicated earlier, the possible relationship between the opiate system and consumption of alcohol has received much attention this past year. In general, the opiate agonists tend to increase drinking of ethanol, since morphine (77, 183, 354, 355) and fentanyl (77) stimulated it. A large dose (20 mg/kg) of morphine, however, inhibited intake of alcohol in rats (354). Chronic administration of morphine also stimulated consumption of alcohol (183,355), suggesting that an opiate surfeit might produce excessive intake of it. Further support for that notion comes from the fact that plasma concentrations of immunoreactive ~-endorphin were elevated in chronic alcoholics in an acute stage of intoxication (26). Contradictory evidence for the idea was found in a report of a reduction in/3-endorphin of 65% in the CSF of alcoholics (411), although concentrations in plasma and CSF do not always coincide. Similarly, long-term ethanol consumption in hamsters produced a decrease in enkephalin in the basal ganglia (411). Mice with a genetic predisposition for alcohol preference also have an innate brain enkephalin deficiency (39,411), and an enkephalinase inhibitor, which would increase levels of enkephalin in the brain, lowered drinking of alcohol in them (39). The evidence concerning the role of the opiate system here, thus, is anything but clear. The studies using antagonists provide little help in this regard. Diprenorphin, like a low dose of morphine, stimulated intake of alcohol and potentiated morphine's effect, but the antagonist reversed the inhibition produced by a large dose of morphine (354). Naloxone improved the symptoms of acute intoxication in two of twelve alcoholics, indicating that it may be of help in the treatment of some cases of alcoholic coma. Naloxone, however, had no effect on the elevated concentration of ~3-endorphin in those patients (26), making conclusions about the involvement of the opiate system difficult. Blood and brain concentrations of ethanol, however, increased in rats treated with naloxone, perhaps due to the slowing of intestinal transit, thus allowing more ethanol absorption (33). Naltrexone had no effect on alcohol-provoked flushing in whites or orientals (440), but naloxone did reverse the impairment of typing ability by ethanol in flushers although not in nonflushers (220). Opiate antagonists, but not morphine, inhibited audiogenic seizures associated with the ethanol withdrawal syndrome in ethanol-dependent rats, suggesting a biochemical link between ethanol and opiate actions (240). Ethanol produced a naloxone-reversible inhibition of a nicotine-induced rise in plasma arginine-vasopressin secretion, indicating a possible complex interaction between ethanol, nicotine, and the opiate system (63). As mentioned in an earlier section, prenatal exposure to ethanol altered stress-induced analgesia in adulthood in male, but not female, rats (20), suggesting a possible developmental change in the opiate system as a result of the early experience with ethanol. Thus, although there is some evidence of opiate mediation of the consumption of alcohol, the nature of

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that mediation and the relationship between the opiates and ethanol remain confusing. G A S T R O I N T E S T I N A L AND RENAL ACTIVITY

During the early stages of research on the endogenous opiate system, the gastrointestinal (GI) tract was discovered to be rich in opiate receptors. Much of the work done since then has attempted to understand the function of those receptors. Since the antidiarrhea! properties of morphine are well known, some of that research has focused on intestinal motility and its mediation by the opiate system. In general, opiate agonists slow intestinal transit (45, 119, 149, 282, 347,383,447), although the effect was biphasic in one case. The agonists decreased peristalsis during the initial phase, descending relaxation, but increased it during the subsequent ascending contraction phase (149). The effect after naloxone is not as consistent. Naloxone increased descending relaxation and decreased ascending contraction (149) as might be expected, but the antagonist slowed intestinal transit in rats after intragastric administration of ethanol (33). Naloxone also decreased responses to field stimulation and motilin in the canine ileum, but in the jejunum it increased sensitivity to motilin while reducing responses to field stimulation (118). The antagonist increased the frequency of defecation after IV administration in horses (212), indicating an overall opposite reaction to morphine's constipating effect. The effect of the opiates appears to be partly receptor dependent. Mu agonists, morphine and PL 17, inhibited intestinal transit, but DPDPE ([2-D-penicillamine, 5-D-penicillamine] enkephalin) and dynorphin 1-9, delta and kappa agonists respectively, had no effect given SC, suggesting that peripheral receptors do not mediate transit (383). The mu receptors in the intestinal mucosa, not in the muscle layers or nerves, appear to be responsible for the antidiarrheal effect (70). The effect is probably produced by activation of noradrenergic and tryptaminergic systems, since depletion of intestinal stores of the peptides abolished or inhibited the action of morphine (71). Enkephalinase inhibitors, acetorphan and thiorphan, reduced castor oil-induced diarrhea in rat, with the former far more potent than the latter, and with naloxone abolishing the effect of both. Since they had no effect on GI transit, as measured in the charcoal meal test, it was assumed that the suppression was due to a decrease in intestinal secretion rather than of transit (282). Even in morphine-dependent rats, morphine inhibited electrical activity in the colon, duodeno-jejunum, and stomach, and naloxone promoted typical activity (347). In the small intestine, dynorphin caused inhibition, and Met-enkephalin and its analogs produced excitation (119). Similarly, in human volunteers, a Met-enkephalin analog, Hoe 825 (Tyr-D-Lys-Gly-Phe-homocysteine-thiolactone), increased esophageal motility and migrating myoelectric complex activity, probably by an inhibition of the inhibitory nervous system (208). Responses to field stimulation and motilin, however, were reduced by Met-enkephalin (118). Ketamine increased GI transit (401), and kentsin decreased it (117), but since the effect of each was not reversed by naloxone, it was assumed to be nonopiate in nature. An analog of dermorphin, dermorphin Nterminal-tetrapeptide-amide or NTT, produced a naloxonereversible enhancement of contractile activity in the colon, thus suggesting opiate mediation of the response (387). Dermorphin, however, slowed gastric emptying in rats, which was inhibited by hypophysectomy, vagotomy, or adrenalectomy (45), indicating a complex control of gastric motility. Although kentsin suppressed GI transit in vivo, it had no effect on the isolated guinea-pig ileum or the mouse vas def-

erens, indicating a lack of opiate properties (117). DAME (D-Ala2-MetS-enkephalinamide), however, did inhibit fieldstimulated contractions of the guinea-pig ileum (40). Met- and Leu-enkephalin produced tonic contractions in the isolated puppy ileum, and naloxone inhibited spontaneous tonic contractions, suggesting that these peptides might modulate the basal tone of the longitudinal muscle in this preparation (317). The enkephalinase inhibitor, thiorphan, increased contractile responses to field stimulation and shifted the dose-response curve to substance P to lower concentrations, further supporting a role for the endogenous opiates here (378). j3-Casomorphin, however, decreased short-circuit current in the isolated rabbit ileum in a naloxone-reversible manner (407), and DPDPE, DAGO, and U-50,488 produced a decrease in both short-circuit current and transepithelial potential difference in the small intestine of the mouse in vitro, with naloxone blocking the effect of all but U-50,488 (380). Secretion of gastric acid is also modulated by the opiate system. Dermorphin suppressed gastric secretion (153), but its NTT analog increased pentagastrin- or histamine-induced secretion in the conscious dog. The effect was inhibited by naloxone, suggesting probable mediation by mu receptors (387). Naloxone alone had no effect on vagal gastrin release or noncholinergic, nonadrenergic gastrin stimulation, but reduced the noncholinergic gastrin response (7). The antagonist increased release of vasoactive intestinal peptide (VIP), and Met-enkephalin decreased it, but dynorphin had a biphasic effect, inhibiting its release during the descending relaxation but increasing it during ascending contraction (149). Pretreatment with morphine or FK33-824 protected against gastric damage by IP administration of indomethacin, and the protection was reversed by naloxone. It was not, however, related to gastric acid secretion, since antisecretory drugs produced no effect on it (388). The effectiveness of FK33-824 in treating chemotherapyinduced vomiting in cancer patients depended on the type of chemotherapy given. It reduced vomiting in those receiving cisplatin but had no effect or increased vomiting in those receiving epirubicin, and produced an unpleasant feeling of heaviness in the body in all patients, thus limiting its value (265). Naltrexone produced abdominal discomfort and nausea when given orally in increasing doses over three days, for a total of 300 mg, with the incidence of these effects being greater in orientals (8 of 20) than whites (1 of 20) (440). Intracisternal/3-endorphin in rats increased plasma glucose and at high doses, hyperglycemia. Preinjection with naloxone prevented the response, which was thought to be mediated by epinephrine and plasma glucagon (12). The opiate system, thus, seems to be involved in a number of different GI responses. The opiate peptides have also been shown to mediate bladder activity. Morphine increased bladder capacity in patients with spinal cord injury by decreasing the rate of contraction (176,430). The extent of injury was important, since those with complete lesions had a reduced number of contractions, although the threshold and magnitude were unaffected, but in those with incomplete lesions, all measures were improved by the agonist (430). Naloxone, however, had no effect on bladder function in patients with spinal cord injury (438). One characteristic of the syndrome of normal pressure hydrocephalus is urinary incontinence, and it has been speculated that it may be due to a decrease in/3-endorphin in the brain due to mechanical pressure on the third ventricle (187). The rate of bladder contractions was also suppressed by DAGO and DPDPE in rats (94,339), with both naloxone and naloxonazine inhibiting them and stimulating contractions

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when given alone (94). A cyclic analog of somatostatin octapeptide, CTP, antagonized the effect of DPDPE but not DAGO at low doses and of both at higher doses, suggesting opiate antagonist properties for the analog (339). Although mu agonists regularly inhibited contractions of the bladder, kappa agonists were able to do so only at high doses, and U-50,488 had no effect at all, suggesting mediation of this response by the mu receptors (340). The dynorphin analog DAFPHEDYN, [D-AIa2,(F5)Phe4] dynorphin 1-13-NH2, when given 1CV produced diuresis in rats that was antagonized by ICV naloxone or naltrexone, but when given IV, it had no effect (432). Urine output was also increased by the kappa agonists, bremazocine, tifluadom, ethylketazocine, and U-50,488, but not by morphine. WIN 44,441 antagonized the effects (96). ~-Funaltrexamine (~-FUN) did not reverse the action of ethylketazocine, and when given alone increased urine output itself, thus acting like an agonist in this situation (97). Bladder activity, thus, is mediated at least in part by the endogenous opiate system. MENTAL ILLNESS

Early in the history of research with the opiate peptides, there was promise of a relationship between mental illness and the opiate system, with hopes of treating psychological disorders by manipulation of the opiates. Those thoughts seem to have largely been abandoned, partly because of limited success and inconsistent results. In part, this lack of progress might be due to the diversity of illnesses typically classified under single labels, such as schizophrenia or depression. It is probable that the biochemistry of such disorders will not allow any easy confirmation that the endogenous system plays any part in the genesis or symptomatology of them, even though subgroups might respond positively to treatment (135). Most research on this topic in 1987 dealt with depression. Depressed patients had elevated concentrations of plasma/3-endorphin, and the patients responded to placebo treatment with further increases in the peptide. In addition, cortisol but not dexamethasone treatment discriminated depressed patients from controls with respect to their ~-endorphin concentrations, indicating that 13-endorphin may be a useful marker in detecting disturbances in hypothalamo-pituitary-adrenal function among depressed patients (138,287). There was, however, a significant elevation of ~3-endorphin in the plasma of depressed patients who had received electroconvulsive therapy immediately and 24 hours afterward, suggesting that the peptide might be involved in the beneficial effects of the therapy (437). Psychotherapy given to arthritic patients with depressive symptoms produced an increase in plasma/3-endorphin concentrations, with a concomitant improvement of the depression. Since pain was not affected, the pain and depression were independent, and the /3-endorphin seemed to be a marker for stress (36). That was not the case, however, in another study, in which pain patients had higher depression scores than nonpatients, although plasma/3-endorphin was equivalent in both groups (80). It appears, therefore, that 13-endorphin might play a role in the expression of depression, but that role needs to be clarified. The opiate system might also be involved in self-injurious behavior (SIB). Naltrexone decreased the frequency of total SIB in three adolescents who received small doses (0.5-2.0 mg/kg orally). Dose-dependent decreases in SIB were found in the two who were also mentally retarded (175). In a doubleblind study, naloxone eliminated SIB and improved other symptoms, including decreasing anxiety, hallucinations, and

reaction time in an item recognition test in a patient with both SIB and motor and absence petit mal seizures (372). Opiates also have an effect on mood, since fentanyl produced euphoria and sedation (95). Morphine tended to improve mood, and naloxone had the opposite effect in opiate-dependent volunteers, who learned to discriminate morphine, naloxone, and saline in a drug discrimination test. Morphine made things seem better, and naloxone made them worse (346). The increased concentrations of ~-endorphin in plasma after exercise, however, were not related to postexercise reports of anxiety and depression, and there was only a minor change in hostility, suggesting that affective states were not affected by the changes in the peptide (168). LEARNING, MEMORY, AND REWARD

Interest in the effects of the opiate agonists and antagonists on learning and memory increased in 1987, reversing a recent trend. As in previous years, experimental parameters continued to be important determinants of the findings in these complex areas. These included the modulation of acquisition and retention processes of avoidance conditioning, the learned discriminative cue properties of the opiates, the mechanisms of reward by opiates, and the alteration of schedule-induced responding. In a one-way avoidance conditioning task, enkephalins and their analogs (DPDPE) (376) or metabolites (Tyr-Gly and TyrGly-Gly-Phe) (204) impaired acquisition. Since none of the agents affected activity or pain, it was assumed that the effect was a direct modulation of learning. The forced extinction of an inhibitory avoidance task was delayed by ~-endorphin, and the effect was blocked by naloxone (86), suggesting that the opiate agonists interfered with learning in various ways. The antagonists, however, produced less consistent findings. In a bar-press avoidance task, rats given naloxone before training learned more slowly than those given saline. Since there was no difference in tail-flick latencies between the groups, it was assumed that the naloxone affected learning directly, not indirectly through pain perception (323). Naloxone or nalorphine before exposure to the first stage of a passive avoidance task, however, had no effect on test performance, unless the same antagonist was given pretest as well as pretraining. If it were administered both times, there was a slight but nonsignificant improvement in retention, suggesting possible state dependent learning (309). Naloxone also had no effect on forced extinction of a passive avoidance response in rats (86). The mediation of the acquisition of appetitive tasks by the opiate system was also studied. Naloxone given before training slowed the acquisition rate of autoshaping associated with food delivery in rats (289). Although naloxone when given before the learning session had no effect on the amount of food consumed by rats in a new environment on the first day due to neophobia, it did increase the intake the second day, indicating that the naloxone facilitated memory of the eating of that food on previous day (309). Naloxone blocked the impairment produced by chlordiazepoxide of the acquisition of a paradigm of differential reinforcement of low rates of responding (DRL) (414), but it had no effect on its effect on the learning of task with variable-interval reinforcement, indicating the mediation of the action of benzodiazepines by the opiate system might be paradigm specific (413). The mixed agonist-antagonist nalbuphine or dezocine interfered with learning with a multiple schedule for food reward in patas monkeys, but another mixed agent, buprenorphine, had no effect (296), so that the effect was specific to the compound used.

214 The modulation of classical conditioning by the opiate system has also been studied. When administered ICV, DAME inhibited the acquisition of a discrimination between a conditioned stimulus paired with shock and one not paired with it, but if injected into the brainstem or given with naltrexone, there was no effect (167). Morphine, ethylketocyclazocine, and U-50,488 also retarded acquisition of the classical conditioning of the nictitating membrane in rabbits. Naloxone alone had no effect but antagonized the effects of all three agonists, indicating that the response may be mediated by a common receptor (374). Naloxone enhanced suppression of the conditioned response during extinction after fear conditioning in rats, perhaps by making the unconditioned stimulus more painful (426). One form of classical conditioning that received special attention was defensive freezing to contextual stimuli associated with an aversive stimulus. In most situations, naloxone (74) or naltrexone administered before the training session (171,172) increased such freezing. There was one instance in which naloxone had no effect, but morphine eliminated the contextconditioned freezing, suggesting that the morphine might have reduced the nociceptive properties of the aversive stimulus (75). That notion is supported by the finding that naloxone interacted with intensity of the aversive stimulus, perhaps increasing its actual or perceived intensity (74). It is likely that the effect is due to learning and not to a change of activity level, since naltrexone given before the test session did not alter the amount of freezing (172). It appears to be a central effect, since naltrexmethobromide injected systematically had no effect, but given ICV, it enhanced freezing (171). Similarly, naloxone administered before each session facilitated the acquisition of conditioned autoanalgesia, which involves the development of analgesia to context cues previously associated with pain (364). When naltrexone was given before the test for analgesia rather than before the learning periods, it reversed the conditioned analgesia, indicating its opiate nature. Apparently the conditioned analgesia is central, since the quaternary form had an effect only if administered centrally (53). The opiate system also seems to be involved in conditioned taste aversion (CTA), since naltrexone reversed the avoidance of saccharin that had been paired with lithium chloride. Morphine, too, acted as an aversive stimulus, reducing the preference for saccharin when paired with it, but interestingly, morphine reversed the effect of lithium chloride (261). The elusive nature of the opiate involvement was further indicated when only one dose of morphine and one of ethylketocyclazocine were able to reverse the effects of pairing apomorphine with sucrose, and only one dose of DAME was antiaversive for the effect of lithium chloride (38). It appears that the opiate system might be involved in learned helplessness as well, at least in the initial induction of it but not in its later expression. Naloxone given before the initial stress prevented learned helplessness, but if given before the shuttlebox exposure, it had no effect (173). There also might be opiate mediation of habituation of a heart-rate orienting response to novel tones in rabbits. DAME produced more rapid habituation, but DADL and naloxone had no effect on the development of habituation. Naloxone reversed the effect of DAME. None altered retention of the habituation a day later (177). The discriminative cue properties of the opiates received significant attention in 1987. Morphine developed such properties, and the effects were antagonized by naltrexone but not its quaternary form (120), or ~-FUN (122). Ethylketazocine also produced distinctive stimulus properties, antagonized by quadazocine (35,97) and WIN 44,441 (96). Codeine (35), U-50,488,

OLSON, OLSON AND KASTIN and bremazocine (97) likewise had quadazocine-reversible cue properties. Antagonists, like agonists, can also demonstrate stimulus properties, as did naltrexone (121,122). The effect generalized to nalorphine (121) but not to/3-FUN (122). Rats that had morphine paired with a distinctive cue later responded to that cue with the same hyperthermia (377) or activation (313) that the morphine had induced, indicating that the cue had become associated with the actions of morphine. A specialized form of this kind of association is place preference or aversion. The positive or negative compound is presented in a distinctive environment, then the animal is given a choice of that environment or another not associated with the agent. Preference was shown for places that had been paired with morphine (24, 98, 129, 226, 381, 382) or heroin (9,98), even in rats tolerant to morphine (382). Food deprivation increased the place preference (129), as did chronic preexposure to naltrexone hut not concurrent exposure to naltrexone and morphine (24), and lesions of the nucleus accumbens inhibited it (226). Preference also developed for environments associated with DPDPE (381) and ~-endorphin, although pretreatment with naloxone blocked it (9). The kappa agonists U-50,488 (31) and U-69593 (382) produced place aversions, rather than preferences. The kappa antagonist Mr 2266 attenuated the aversion of the former, and vagotomy shifted it to place preference (31), while chronic preexposure to the latter abolished any effect (382). Place aversion was learned for areas associated with naloxone (98), and preference associated with Mr 2266 occurred (31). The delta antagonist ICI 174,864 had no effect itself or with morphine, but inhibited the preference for the environment paired with DPDPE (381). Not only learning, but memory as well, seems to be mediated by the opiate system. In general, the opiate agonists interfere with retention (195, 327,456), and the antagonists facilitate it (110, 196, 197, 202, 310, 456) when given immediately after training. The amnesia produced by Leu-enkephalin and DPLPE, but not that of ~-endorphin, in a one-trial taste avoidance paradigm was reversed by the delta antagonist ICI 174,864 (327). Although dynorphin 1-13 lowered retention of an inhibitory avoidance response when given post training, it did not affect retention of it when administered pretest, and it had no effect on memory of habituation or a Y maze 095). Retention of both inhibitory avoidance and Y-maze tasks was decreased by Met-enkephalin, in a naloxone-reversible manner. The enkephalin also reversed the facilitation of naloxone, but adrenal denervation had no effect on the opiate modulation (456). Immediate posttraining administration of naloxone improved retention in chicks and mice, with the ICV route producing 1000-fold more potency than the SC route. The antagonist had an inverted U dose-response curve, with high doses suppressing retention. Naloxone also blocked the amnestic effects of scopolamine and anisomycin in mice (110). Antagonists blocked the interference produced by high doses of epinephrine (I 96,202) and potentiated the facilitation of low doses (196). Naltrexone given immediately posttraining improved retention tested at six but not at three hours after training, indicating timing as a critical variable (202). Naloxone into the amygdala (197,310) or given IP (197) facilitated retention, hut if injected into the caudate-putamen or cortex, it had no effect (310)./3-Noradrenergic blockers but not c~-adrenergic antagonists into the amygdala inhibited the effect of naloxone, suggesting that mediation is through the/3-noradrenergic receptors (197). The disruption of memory by electroconvulsive shock (ECS) was blocked if either ~3-endorphin or another ECS were given before the test ECS, suggesting possible state-dependent effects

OPIATES: 1987 mediated by ~-endorphin (314). Another study, however, found that administration of/3-endorphin did not affect retention of a passive avoidance in intact rats or rats with ECS-induced amnesia. Acute injection of naloxone also had no effect on ECS-induced amnesia, but continuous infusion of the antagonist abolished it (199). Capsaicin increased retention of a passive avoidance task, and since it altered pain perception as well, it might have an opiate mechanism for both actions (254). Performance of a learned task, as well as acquisition of it, is affected by the opiate system. Although both agonists and antagonists tended to disrupt responding, the specific parameters being manipulated affected the outcome. Agonists for mu, sigma, and kappa receptors all inhibited responding on a chained schedule if there were a discriminative stimulus for the first component, but they had no effect without the stimulus. Naloxone and bremazocine had no effect with or without it (331). Morphine, ethylketocyclazocine, U-50,488, and naloxone decreased the rate of responding but not its accuracy, and phencyclidine and (+) N-allynormetazocine reduced both (332). Morphine either improved performance or had no effect, depending on dose (131). Both amphetamine and naloxone suppressed responding on a fixed ratio schedule, and the actions of the two were additive. On a fixed interval schedule, however, independently each had no effect, although together they had an inhibitory one, so that the type of procedure used is important (l 1). A quaternary form of naltrexone given systemically suppressed responding in both fixed ratio and variable interval schedules in pigeons, however (120). Although naltrexone had no effect on bar pressing on a concurrent schedule (131,15 l), it did disrupt responding on a variable interval schedule (120). Naloxone inhibited responding with a multiple schedule with signalled unpunished and punished periods in rats (56). Methylnaloxone centrally administered and naloxone injected SC reduced responding for food in morphine-dependent rats (237). In a shock titration paradigm, a single dose of naloxone lowered the shock level and increased response rates, and although chronic administration of it also stimulated response rates, it had no effect on the shock level (321). Naloxone had no effect on the suppression of responding induced by chlordiazepoxide on either a variable interval (413) or DRL (414) schedule, but the two in combination did alter behavior on a multiple schedule with punished and unpunished periods. Responding was increased in the unpunished segment and was unaffected in the punished one, indicating the emotional component was an important factor. Valproic acid with naloxone decreased responding in both periods (56). Naloxone potentiated the suppressive effects of phenylethylamine, specifically reducing the motor behavior of the learned response (146). The mixed agonist-antagonist nalbuphine or dezocine also suppressed responding for food in monkeys, but buprenorphine had no effect (296). The reward value of the opiate agonists has been studied to determine its mechanisms. Naloxone inhibited but did not completely block cocaine's lowering of the threshold for brain stimulation to the median forebrain bundle or ventral tegmental area in rats, indicating an interaction between the opiate and catecholamine systems in reward function (19). Lesions of the nucleus accumbens attenuated morphine's reward, decreasing place preference for the area associated with morphine (226). Injections of methylnaloxonium into the nucleus accumbens produced a dramatic suppression of operant responding, further suggesting that the receptors in that area may be responsible for the reinforcing properties of the opiates (237). In vitro reinforcement of cells in CA3 of the hippocampus was pro-

215 duced by U-50,488 and dynorphin A, as indicated by an increase in frequency of bursts of responding, but Leu-enkephalin had no effect (391), suggesting the enkephalin did not play a role in reward in the hippocampus. Naloxone was aversive, since mice avoided cues paired with ( - ) but not (+) naloxone (306), perhaps due to antagonism of the endogenous opiate system. CARDIOVASCULARRESPONSES Although vast amounts of research have been done concerning the possible role of the opiate system in cardiovascular function, little is known about its normal role. Opiate peptides and receptors have been found in the cardiovascular system, and they appear to be involved in central cardiovascular regulation, but it is difficult to draw conclusions about their physiological effects because of inconsistent results. Responses to the administration of opiate agonists and antagonists depend on species, route of administration, use of anesthesia, and selectivity for receptor subtypes. Current data suggest that the opiate system might have a role in cardiovascular stress responses, particularly shock (107). Blood pressure is one of the most frequently used measures of cardiovascular functioning. Morphine produced a profound decrease in blood pressure (227, 399, 406) that was transient (406). Subsequent naloxone reversed the effect (227,406), but pretreatment with the antagonist had no effect (227). In morphine-dependent rats, however, injection of morphine raised blood pressure, and subsequent naloxone increased it further (406). Morphine also increased blood pressure in opiate-dependent humans (346). Morphine did not, however, change the baroreflex to pharmacological alteration of blood pressure by phenylephrine hydrochloride and sodium nitroprusside (399). Fentanyl produced hypotension in anesthetized rats, and physostigmine reversed the depression, suggesting a cholinergic mechanism (442). Naloxone and nalbuphine increased blood pressure after surgery with fentanyl, indicating possible opiate mediation (18), so that there may be an interaction between the opiate and cholinergic systems for this drug. The endogenous opiate peptide Met-enkephalin raised blood pressure in patients with cardiac catherization for chest pain but no apparent disease, with naloxone reversing the effect (136). The Met-enkephalin analog FK 33-824 also produced elevation of blood pressure in normal guinea pigs when administered ICV (352), indicating consistent effects across species, conditions, and route of administration of the two enkephalins. The action of dynorphin 1-13 was affected by route of administration, however, since IV injections lowered blood pressure and ICV administration increased it in unanesthetized rats (139). Centrally administered ~-endorphin produced hypotension in both normal and spontaneously hypertensive rats (SHR) (300). As in previous years, in 1987 it appeared that the opiate antagonists produced more consistent findings than the agonists. Naloxone alone under a variety of conditions was typically found to have no effect on blood pressure (11 l, 166, 253, 284, 399), although it did increase blood pressure in newborn lambs given the antagonist just before birth (325) and did produce severe hypertension during labor in one patient with previous mild hypertension (375), perhaps due to an alteration of the opiate system during parturition. The presence of cirrhosis in humans or rats did not alter the inability of naloxone to affect blood pressure (253), and the antagonist did not affect established hypertension due to long-term isolation, deoxycorticosterone acetate, or genetic factors (SHR) (11 l). Naltrexone blocked the hypotensive response that followed

216 the pressor response induced by stress, and naloxone attenuated the pressor response itself (284). Naloxone also decreased the baroreflex to pharmacological intervention by phenylephrine hydrocloride and sodium nitroprusside (399). The antagonist inhibited the hypertension produced by the contrast medium sodium/meglumine diatrizoate but not iohexol, indicting a possible role for the endogenous opiate system in blood pressure changes associated with the former (166). Naloxone also decreased the hypotension produced by clonidine in SHR (286,300), although its effect on normotensive rats was inconsistent. One study found that it did not alter ICV clonidine's effect in Wistar-Kyoto rats (286), but another reported that it suppressed the hypotension of clonidine in Sprague-Dawley rats (300). Findings similar to those found for measures of blood pressure were reported for heart rate. Morphine decreased heart rate in rats (139,406), dogs (399), and rabbits (182), and subsequent naloxone (406) or dynorphin pretreatment (139) reversed the effect. In opiate-dependent humans, morphine had no effect on heart rate (346). Chronic morphine for three days eliminated the response to acute morphine, but if continued for six days, an acute dose produced increased heart rate. Thus, acute and chronic effects differ (406). Fentanyl produced bradycardia, which was reversed by physostigmine (442), naloxone, or nalbuphine (18), further supporting an interaction between the cholinergic and opiate systems. Met-enkephalin increased heart rate initially for patients cardiocatherized for chest pain but with no known cardiac disease (136), but its analog FK 33-824 administered ICV decreased heart rate in guinea pigs (352), so that although the two had the same effect on blood pressure, they had divergent actions on heart rate. At high doses, FK 33-824 produced bradyarrhythmias that sometimes were fatal (352). Similarly, although dynorphin 1-13 altered blood pressure depending on route of administration, it had no effect on heart rate, regardless of route (139). In conscious dogs, intracisternal DADLE produced an atropine-reversible bradycardia (156), but in rabbits, IV DADLE and DAME induced naloxone-reversible tachycardia (177), so it is not clear whether route, species, or another factor was critical here. Naloxone did not have as consistent results with measures of heart rate as it did with blood pressure. The antagonist had no effect on heart rate in some cases (253,284, 399) but raised it in others (13, 177, 212, 325). The speeding of heart rate was seen in the human fetus near term (13) and in the newborn lamb (325), suggesting, as with blood pressure, that changes in the opiate system near birth produce cardiovascular effects. Quaternary naloxone reduced heart rate, however, inducing the opposite effect from the tertiary form (177). Naltrexone and naloxone also had opposite effects after stress in rats, with the former attenuating and the latter potentiating the tachycardia resulting from restraint (284). Naloxone reversed the bradycardia produced by clonidine in SHR (286,300) and SpragueDawley rats (300) but not in Wistar-Kyoto rats (286). Regional blood flow is also mediated to some extent by the opiate system. In rats, heroin significantly increased regional cerebral blood flow to 21 of the 40 areas studied, and the response was naloxone reversible. Naloxone alone reduced blood flow in one of the 40 areas, the entorhinal cortex (415). Dynorphin 1-13 produced dose-related reductions in blood flow to the thoracic and lumbosacral spinal cord, but dynorphin 3-13 lowered it only to the latter. Naloxone did not alter the effect (268). Hepatic and azygos blood flows were unaffected by naloxone in both humans and rats with or without cirrhosis, indicating lack of opiate mediation of hemodynamics in the disease (253).

OLSON, OLSON AND KASTIN The involvement of the opiate system in cardiovascular responses can also be seen by measuring the concentrations of the peptides in the body. Premature infants who had low pressure had higher concentrations of immunoreactive 3-endorphin in the plasma at six hours after birth (82), suggesting a possible mechanism for the hypotension. Plasma 3-endorphin was lowered more in SHR than in Wistar-Kyoto rats after clonidine, but the concentration of the peptide was higher in the neurointermediate pituitary in SHR. Clonidine did not affect 3-endorphin in the anterior pituitary, however (448). Baseline concentrations of plasma 3-endorphin and those resulting from stress were similar in SHR and Wistar-Kyoto rats, indicating that the peptide was an unlikely cause of the hypertension in SHR (49). Although nicotine increased plasma enkephalinlike immunoreactivity, it did not alter heart rate and blood pressure, indicating a possible reason why smoking may not produce hypertension (179). The heightened opiate activity associated with congestive heart failure, as measured by increased plasma 3-endorphin, might mediate the cardiovascular changes that also occur, including increased blood pressure, decreased cardiac output, and tachycardia (260). The opiate peptides also affect cardiovascular functioning in vitro. Morphine, Leu-, and Met-enkephalin produce an initial decrease then increase in coronary pressure and a decrease in heart rate in the isolated rat heart. Naloxone has similar effects, without the initial lowering of coronary pressure (423). In the sarcolemmal membrane from bovine heart muscle, Met-, Leu-enkephalin, and morphine inhibited ion movement, thereby affecting myocardial contractility (424). In isolated rat atria, none of the opiate peptides tested, including Met- and Leu-enkephalin, Met-enkephalin analogs, 3-endorphin, and dynorphin, had any effect on atrial tension with electrical stimulation, suggesting that circulating endogenous opiates probably do not have any direct effects of rat myocardium to affect myocardial contractility (441). More research needs to be done to clarify the situation. In the past and in 1987, much attention was focused on the possible role of the opiate system in mediating effects of cardiovascular shock. As in the past, experimental variables were critical to the results, with the kind of shock being particularly important, although inconsistent findings were reported even within that manipulation. With hemorrhagic shock, plasma 3endorphin increased and peaked at the nadir of blood pressure (319). Plasma Met-enkephalin-like immunoreactivity also rose after bleeding, with the effect being greater in intact than in adrenalectomized rats. There were, however, similar decreases in blood pressure in the lesioned and sham-operated rats (194). If the level of circulating opiate peptides increases during hemorrhagic shock, it would seem logical that naloxone would be helpful in treatment. That was not always the case, although it did raise blood pressure in some studies (191,227) but not to prebled values (227). Reinfusion of blood raised blood pressure, and the elevation was maintained by naloxone but not by saline. Naloxone also promoted reperfusion into capillaries and significantly increased survival rate (457). Since captopril and saralasin impeded naloxone's reversal of hemorrhagic hypotension, it is possible that there is an interaction between the opiates and angiotensin in this response (191). With adrenalectomy, naloxone was less effective in reversing the shock, suggesting that depressor opiate peptides from the adrenals might mediate hypovolemic shock (227). There were contradictory findings, as well, with some reports of no benefit with naloxone after hemorrhage. It did not alter blood pressure in hemorrhagic shock in sheep (55) or dogs (155), nor did it alter heart rate in sheep (55). It did, however,

OPIATES: 1987 produce bradycardia in rabbits after hemorrhage (368). Thus, the role of the opiate system in shock after bleeding has become less clear in the last year. Similar inconsistencies were found with septic shock. One study reported increased concentrations of plasma 13-endorphin, Met-, and Leu-enkephalin in dogs exposed to endotoxic shock. Naloxone did not alter these values (288). With human patients, concentrations of /3-endorphin did not differ between those suffering from shock (including cardiogeneic, intoxication, and septic shock) and the nonshock controls (8). The ability of naloxone to reverse the effects of the shock was more consistent, however, since the antagonist increased blood pressure and cardiac output in dogs (155), prevented lowering of cardiac output after infusion with E. coli in piglets (64), blocked the reduction of blood flow to the cerebellum and midbrain in rats, although it had no effect on blood flow to the whole brain (249), and increased blood pressure in two of seven human patients with septic shock (8). Naloxone did not alter cardiovascular functioning in patients with shock associated with intoxication or cardiomyopathy (8). Met- and Leu-enkephalin suppressed the development of anaphylactic shock after ovalbumin in conscious rats, with the former completely protecting against shock with a single injection. Leu-enkephalin required ten injections before blocking the shock (205). Thus, it appears that the opiate system has a role in the cardiovascular symptoms of shock, but that role has not yet been delineated fully. RESPIRATION AND THERMOREGULAT1ON

The trend of past years of declining interests in the possible mediation of respiration and thermoregulation by the endogenous opiate system continued in 1987. Not much research was done on the effects of the opiate agonists and antagonists on respiration, but there was some work done on their influence on respiratory disorders and development. As typically found, morphine lowered respiratory rate, with repeated injections producing rapid tolerance and consequent lessening of the effect (182,343), unless naloxone was given at the peak of morphine's action, thus preventing the development of tolerance (182). In opiate-dependent humans, morphine did not alter respiration. Naloxone, however, also had no effect, although it is possible that measure was taken after too long a period after the injection, thus missing the response (346). Like morphine, DADLE decreased respiration in dogs (156). Naloxone, as expected, did the opposite, increasing respiratory rate in cats (315) and horses (212), although it had no effect in rats (322). Contractions of the isolated guinea pig bronchus were inhibited by the enkephalin analog [D-Met2,ProS]-enkephalinamide. Naloxone reversed the effect but had no effect itself (28). Ketamine (337) and fentanyl (18,442) lowered respiratory output, and since the former was not reversed by naloxone (337), it might not be mediated by the opiate receptors. Physostigmine inhibited the respiratory depression of fentanyl, suggesting a cholinergic mechanism for the action (442). Both naloxone and nalbuphine restored normal ventilation after fentanyl (18), however, indicating possible opiate involvement. Massive doses of naloxone given for treatment of spinal cord injury up to 30 min before surgery produced highly irregular responses to fentanyl given during the surgery, including hyperventilation, hypertension, and shallow anesthesia (34), supporting the idea that the opiate system modulates the effects of fentanyl. The underlying control of fentanyl, thus, is likely to be a complex one.

217 In conscious rats, naloxone potentiated the hyperventilation and progressive decrease in respiratory function resulting from hypoxia (322), but in anesthetized cats, it inhibited the amount of ventilatory depression and did not alter ventral medullary surface pH (315). In fetal lambs undergoing hypercapnia, naloxone had no effect (210), indicating that the action of the antagonist in situations of respiratory distress is dependent on a variety of conditions. In human patients with chronic obstructive pulmonary disease, naloxone did not alter baseline respiration (362), so that the opiate system probably does not play a role in it. Since naloxone did block the ventilatory depression and increase survival rate after infusion of E. Coli in piglets (64), the endogenous opiates might be involved in the respiratory response to septic shock. The opiate system also seems to mediate some forms of neonatal asphyxia, since concentrations of immunoreactive/3endorphin were elevated in the plasma of premature infants with moderate or severe asphyxia during the first six hours of life. There was, however, no difference in the peptide concentration for the presence or absence of apnea (82). There was a significant rise in 13-endorphin in the CSF in infants with proven apnea, with histories of apparent life-threatening events, or with siblings who were victims of Sudden Infant Death Syndrome. Plasma concentrations of the peptide did not correlate with those in CSF, indicating an explanation for the discrepancy between the studies and suggesting that elevation of CSF /3-endorphin might be a marker for apnea in infants (308). The endogenous opiate peptides seem to influence fetal lung maturation, enhancing the development. Morphine given to pregnant rabbits increased and naloxone suppressed lung function in the fetuses (67). The opiate system appears to modulate breathing most shortly after birth (at four days as opposed to 10-18 days of age) in piglets in normoxia, but during hypoxia, they modulate respiration at both ages (301). In lambs in utero, naloxone increased the amplitude but not the incidence or rate of fetal breathing, especially during hypercapnia (210), perhaps due to the release of opiates during the stress. Studies in 1987 dealing with temperature regulation focused on experimental parameters affecting the action of the opiates after their administration, with the exception of one that dealt with possible mediation of hypothalamic thermoregulation processes by ~-endorphin. The concentration of the peptide in plasma was lowest at the onset of menopausal hot flushes, with a significant rise in it up to 15 min afterward (403). One of the variables studied for the timetable of hyperthermia after morphine depended on the measurement site, with rectal temperature reacting more quickly than tail temperature and only the former being naloxone reversible. Both/3-endorphin and morphine had a greater effect on rectal than on tail temperature (343). Diet also affected the hyperthermic response to morphine by rats. The greater the percentage of protein in the diet (from 4-50% ), the stronger the response to the drug (37). The specific compound tested seemed important, since one enkephalin dimer produced a naloxone-reversible, short-lasting hypothermia in mice, but another one had no effect (236). Similarly, /3-endorphin and 13-endorphin 1-27 produced dose-related hypothermia with different durations, and the latter attenuated the effect of the former, indicating both agonist and antagonist effects for the latter (397). The diurnal rhythm did not affect the biphasic thermal response (hypothermia then hyperthermia) of naltrexone and naloxone in rats, since the responses were equivalent during the day and at night (100). Chronic administration of morphine produced tolerance to both the initial hypothermic and later hyperthermic reactions to morphine. The latter finding had not previously been re-

218

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ported, probably due to lack of systematic investigations of morphine hyperthermia (305). In rats, repeated administration of morphine or 3-endorphin increased the elevation of rectal temperature, thus indicating no tolerance for that response even though there was for other behavioral measures (343). In opiate-dependent humans, however, tolerance was clearly seen, since morphine had no effect on temperature. Naloxone, too, did not alter temperature, confusing the picture somewhat (346). The ambient temperature greatly altered the thermal response to morphine, with the drug producing hypothermia in normal room temperature but not in a warm environment (305). Dermorphin induced hypothermia in a cold environment and hyperthermia at 22°C or higher, and pretreatment with naloxone completely blocked both effects (44). The kappa agonist U-50,488 combined with a neuroleptic produced poikilothermia, having the body temperature approximate the ambient one. The condition was lethal when the animal was housed in ambient temperatures of 5 ° or 35°C. The investigators suggested that poikilothermia could be advantageous in situations in which slowing of the metabolism was desirable, such as during cardiac surgery, protection of the CNS after stroke, neardrowning syndrome, or space travel (5). SEIZURES AND OTHER NEUROLOGICAL DISORDERS

In 1987 interest remained high in the possible mediation of seizure activity by the endogenous opiate system. In general, opiate agonists, when administered directly into the brain, produced seizures. Microinjection of morphine (25-50 nmol) into the rat amygdala at higher doses produced motor limbic seizures and status epilepticus, although at lower doses it resulted only in staring, gustatory automatisms and wet dog shakes (WDS). There were also epileptiform changes in the electroencephalogram (EEG) recordings after the higher doses, as well as seizure-related damage to a number of brain areas. The enkephalin analog DADLE had effects similar to the lower doses of morphine, except that pretreatment with naloxone blocked the actions of the former but not the latter (188). When administered to the ventral hippocampus both DADLE and PL 17 produced convulsive seizures and WDS, but PL 17 to the dorsal hippocampus, frontal cortex, or striatum had no effect, suggesting that the opiate peptides might regulate hippocampal excitation. Pretreatment with 3-FUN attenuated the effects of PL 17 (252). Both DADLE (a mixed mu and delta agonist) and DAGO (a mu agonist), but not DPDPE and DPLPE ([2-D-penicillamine, 5-L-pencillamine] enkephalin) (both delta agonists), given ICV, produced EEG seizures but no behavioral convulsions in unanesthetized rats. They were antagonized by naloxone and 3-FUN (both mu antagonists) but not by IC1 174,864 (a delta agonist), indicating that the effect is probably mediated by mu and not by kappa receptors (410). In anesthetized rats, however, a different delta agonist (DSLET) induced epileptiform electrocorticogram seizures and myoclonic contractions that were blocked by delta antagonists but not by naloxone, so that a delta component to mediation of seizures was shown here (157). It is possible that the anesthetic given to the rats in one study but not the other accounted for the differential findings. Interestingly, the agonists have also been shown to have protective effects against repeated seizures elicited by other stimuli. Both U-50,488 and DAGO had anticonvulsant properties against convulsions produced by transauricular supramaximal electroshock in rats (409). Protection by U-50,488 against seizures induced by kainic acid was not as great, with no effect

after central administration of the kainic acid but with a decrease in WDS and degeneration of hippocampal neurons after IP kainic acid. There was no protection in the latter case against status epilepticus or neural degeneration in other brain areas, especially the entorhinal cortex (248). Although morphine had no effect on the incidence of the first seizure, it did decrease the probability of a second seizure in genetically epileptic hamsters. The protective effect of morphine was reversed by naloxone. The endogenous opiate system might be involved in this seizure activity, therefore (344). The opiate antagonists in some cases had epileptogenic properties, possibly supporting an inhibitory role for the endogenous opiate system in seizures. Naloxone given ICV (100-1000 nmol) had effects similar to those of morphine, with motor seizures, EEG seizures, and status epilepticus resulting (188). High doses of naltrexone methylbromide into the preoptic area, zona incerta, or corpus callosum produced convulsions and body shakes (417). Repeated IP injections of naloxone given every 15 min (8 mg/kg) produced seizures and status epilepticus alone or when paired with a photoacoustic stimulation that by itself had no effect. The responses to repeated naloxone were similar to those in amygdala kindling (363). In other studies, antagonists have been shown to have beneficial effects, with naltrexone and naloxone reducing postictal behavioral depression in amygdala kindled rats (69). Naloxone blocked the spreading depression after seizures caused by ECS or potassium chloride and reversed cell refractoriness afterward in seizure-sensitive Mongolian gerbils (152), suggesting possible opiate mediation of the epilepsy. The total number of afterdischarges to kindle general convulsions by electrical stimulation of the amygdala was increased by naloxone, and the maximal seizure stage was decreased, although nonsignificantly (50). In still other cases, naloxone did not affect seizure activity at all. The afterdischarge (264), postictal depression, and WDS (422) after electrical stimulation of the hippocampus in rats were not altered by ualoxone. Likewise, postictal depression after convulsions elicited by air blast to the back of gerbils was not reversed by naloxone or naltrexone (123), nor were WDS induced by electrical stimulation of the hippocampus altered by 3-FUN or ICI 174864 (295). Support for the idea that the opiate system plays a role in epileptic activity comes from reports of alterations in peptide concentrations or binding after seizures. The concentration of immunoreactive proenkephalin mRNA increased after kainic acid-induced seizures or WDS in rats. The concentration correlated with the number of WDS, and the changes in it occurred from the onset of shaking. Hippocampal enkephalins rose initially then fell, indicating that the rate of precursor processing and peptide utilization was increased by the seizure activity (184). Several receptor types seem to be involved since kindled seizures released mu, kappa, and delta agonists, and naloxone partially reversed the postictal changes (54). After hippocampal formation kindling in rats, binding for mu and delta receptors in the hippocampus was inhibited, although the effect was transient, lasting one day for mu binding and seven days for delta binding (72). In human patients, CSF concentrations of 3-endorphin were elevated postictally, returning to normal within one to four days afterward (335). The number of opiate receptors was increased in some regions of decreased glucose utilization in patients with temporal lobe epilepsy, on the same side as the seizure focus, suggesting a possible component to an endogenous anticonvulsant system mediated by the opiate peptides (127). There was not, however, a long-term interaction between 3-endorphin and the anticonvulsant drug ,y-vinyl-GABA (GVG),

OPIATES: 1987 since patients with complex partial epilepsy who were given GVG had a slight increase in CSF /3-endorphin after three months but not after six months (334). The role of the opiate system in the mediation of seizures remains to be delineated. Attention has also been focused on the involvement of the endogenous opiates in spinal cord injury, although the results are anything but conclusive. Intrathecal (IT) dynorphin produced a rather specific neurotoxic action in the spinal cord, killing neurons in the ventral horn but doing no damage to those in the dorsal horn, suggesting that dynorphin might be responsible for the degenerative processes associated with spinal injury (60). Similarly, IT dynorphin caused paralysis and a loss of neurons through the lumbosacral spinal cord (268). Naloxone, however, had no effect on the integrity of the cord as measured by spinal evoked potentials after trauma to the cord (160). Even if it were effective, caution was urged in using naloxone as a treatment for such injury, since the antagonist altered the activity of anesthetics given later for surgery (340), as mentioned earlier. In spinal cord lesion patients, morphine suppressed EMG discharges and reduced spasticity given either IT as bolus or as chronic infusion, indicating therapeutic benefit for the patients (176). The opiate peptides may play a role in regeneration and development of nervous tissue, since Leu-, Met-enkephalin,/3-, "r-endorphin, and analogs of Leu-enkephalin promoted growth of cultures of rat sympathetic ganglia. Spinal cord and dorsal root ganglia cultures were also stimulated by Leu-enkephalin or an analog (190). The action potentials from explants of dorsal root ganglion spinal cord of fetal mice were inhibited by acute administration and excited by chronic administration of DADLE (73), indicating opiate mediation of those cells. Brain injury, like spinal injury, has been shown to be influenced by the opiate system. After transient bilateral carotid artery occlusion in the gerbil, there was a lasting change in dynorphin A concentrations in the hippocampus, with up to a 50°70 decrease in the peptide for up to at least a week. The hippocampus, thus, appears to be particularly vulnerable to ischemia, with unique sensitivity for dynorphin (124). After fluid-percussion brain injury in cats, dynorphin A accumulated in the injury regions (274,275), especially those showing a decrease in cerebral blood flow (274). The antagonist WIN 44,441-2 and -3 improved survival and decreased the symptoms (274). After fluid-percussion injury in cats, there was also a decrease in B-endorphin in the hypothalamus, but no change in Leu-enkephalin in any brain tissues studied. The greatest changes appeared to be the increase in dynorphin, suggesting a role for it in the pathophysiology of brain injury (275). In two patients with postconcussional syndrome who did not respond to any other treatment, naltrexone improved the symptoms. The findings were preliminary, since one study was a singleblind experiment, but the results were encouraging (402), and indicated that the opiate system might be responsible for prolonging the symptoms. In normal pressure hydrocephalus, the areas of the brain affected are rich in opiates, and the pressure might alter activation of the endogenous opiate system, producing the symptoms of the disease (187). In tardive dyskinesia in chronic schizophrenia, naloxone produced dramatic improvements in three of thirteen patients, with the dyskinesia being completely abolished in two of them. The improvements, however, diminished after one hour and occurred only in those patients whose dyskinesia was of short duration (41). The opiate system, thus, may be involved in some way in this disorder, as well as in Werdnig-Hoffman's disease, since the brain of an infant who died of the latter had low concentrations of/3-endorphin in all

219 areas studied (326). It is less likely that the opiate system mediated the symptoms of Gilles de la Tourette Syndrome, with administration of naloxone having no beneficial effect. There was a decrease in vocalization and head shaking, hut an increase in facial tics, with the total number of tics unchanged (128). In Alzheimer's disease, all areas affected are rich in/3-endorphin and enkephalin-like substances. There is a decrease in/3endorphin in the CSF that is correlated with the severity of the dementia (186,209). Alzheimer's patients had increased binding of kappa receptors in all areas examined, and the amygdala had decreased mu and delta binding. Total binding in the frontal cortex, caudate, and hippocampus was unaffected, but in the putamen was increased in Alzheimer's brains (180). Although there are changes in the opiate system in the disease, its exact role in the symptomoiogy is not known. The involvement of the opiate peptides in Parkinson's disease is less clear. There was one report of lowered CSF/3-endorphin in untreated Parkinson's and autistic patients (186), but another found no difference between controls and individuals with Parkinson's in CSF /3-endorphin (209). Lesions found in Korsakoff's syndrome are found in opiate rich areas, indicating a possible link between the disorder and the opiate system. For all these CNS diseases, evidence linking them to opiate mediation is preliminary at best. ELECTRICAL-RELATEDACTIVITY Activity of the opiate agonists and antagonists has often been studied in one of several in vitro assays, including the electrical stimulation of the guinea-pig ileum, which was discussed in the GI section of this paper, and of the mouse vas deferens. Differential potencies for human, camel, turkey, ostrich, horse, and salmon B-endorphin were found in several different assays. In the mouse vas deferens, the human form was more potent than all others. In the rat vas deferens, mammalian forms were more potent than those from birds or fish, and activity in this assay correlated with analgesic potency. In the rabbit vas deferens, all were weak. There was no correlation between binding activity and any of the assays, however (181). Diprenorphine was found to be an agonist at kappa receptors in the guinea-pig ileum but an antagonist at the mu receptors there. It was also an antagonist at the delta receptors in the hamster vas deferens, at kappa receptors in the rabbit vas deferens, and at mu receptors in the rat vas deferens, indicating a complex mechanism for its actions (412). In isolated tail arteries of rats, perfusion with a wide variety of opiate agonists inhibited contractions to field stimulation, with/3-endorphin producing the strongest effect and the kappa agonists having a weak action if at all. The effects of all but the kappa agonists were naloxone reversible (189). The activity of single cells or areas of the brain after administration of opiate agonists or antagonists has also been studied frequently. An area that received much attention in 1987 was the hippocampus, although not all parts of the structure reacted in the same way. DADLE and Leu-enkephalin increased the primary population spikes and excitatory postsynaptic potentials (EPSPs) in the CA3 region (87). When cells from the same region were perfused with U-50,488 in vitro, their synaptic activities were decreased, probably by inhibition of a subtype of the sodium channel (200). In cells from CA1 and CA3, dynorphin had no effect on the resting membrane in a majority, but in those that did respond, there were more spikes and a shift in spontaneous firing from single spikes to bursts (370). In the CAI area, there was an increase in ampli-

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tude of population spikes in the stratum pyramidale but no effect in the stratum radiatum after DAGO in vitro, and the excitation was reversed with naltrexone (302). Although cells in the CA1 area responded only to mu and delta agonists, those in the dentate were excited by mu, delta, and kappa agonists (316). When DAME was applied to the dentate gyrus in vivo, the amplitude of population spikes evoked by stimulation of perforant path increased, but there was a reduction of recurrent inhibition as well as inhibition of spontaneous activation of individual granule cells. This action was antagonized by naloxone, indicating opiate responsiveness here, but paradoxical inhibition of spontaneous unit activity (439). Cellular activity in the nucleus accumbens was mixed after heroin and morphine in rats, with most cells being depressed, but some excited and others unaffected. There was no effect from these drugs on evoked potentials (161). Heterogeneity of cell activity also occurred in response to dynorphin 1-8 in the substantia nigra. Dynorphin inhibited 22%o of the neurons with rapid onset and offset and 22% of those with slow onset and offset, with no effect on the remaining ones. The peptide also attenuated the inhibition of GABA in that area, indicating contradictory actions for it (359). Morphine inhibited the spontaneous discharge in the locus coeruleus in both anesthetized and conscious rats, with the effect ten times more potent in the former. Higher doses of morphine were needed to suppress the excitation induced by footshock (420). The action potential of neuroblastoma cells was decreased by DADLE in both duration and amplitude, but the resting potential, rise time, and input resistance were unaffected. Naloxone alone was ineffective, but it did block the effects of DADLE (85). Since the activation of sensory neurons in the isolated rabbit ear by capsaicin or acetylcholine was not influenced by an analog of Met-enkephalin, apparently the action was not mediated by the opiate system (28). The dorsal root evoked potentials of neonatal spinal cord in the rat were, however, sensitive to opiate modulation, with all of the agonists tested producing dose-dependent depressions. The delta agonists and some of the kappa ones produced weak and inconsistent results, but the mu ones were strong, suggesting probable mu mediation. This notion was further supported by the finding that naloxone but not ICI 174,864 attenuated the depressions (43). Since both aspartate antagonists and DAGO produced similar depressions of synaptic transmission in the rat spinal dorsal horn, opiates appeared to modulate excitatory amino acid synaptic actions that were mediated by aspartate receptors (206). LOCOMOTOR ACTIVITY

In 1987 interest in the ability of the opiate peptides and antagonists to modulate the general activity level of organisms remained high. As in the past, and as with other topics covered in this paper, experimental parameters were particularly crucial to the observed effects, making generalizations about the effects difficult. Many of the peptides have biphasic effects, first decreasing then increasing activity, and many have opposite actions at different doses. Route of administration and species differences further affect the opiate mediation of the behavior, as do the specific receptor type activated and the behavioral measure used. The effect of morphine on locomotion was widely studied in 1987, and generally the agonist increased it (24, 54, 192, 219, 221,258, 291,313), as did heroin (419). Hyperactivity was also produced by /3-endorphin (9), DPDPE (291), and U-50,488 (101), although the latter was also reported to decrease locomo-

tion in some cases (101,221) and to have no effect in others (101,178). DPDPE was also found to have no effect in an open field after shock (376), and ~-endorphin decreased open-field behavior (443), thus having inconsistent results for many of the peptides. Other agonists were found to have no effect on locomotion, including Leu-enkephalin (204,376) and PD 117303 (178), and although one metabolite of Leu-enkephalin did not alter it, another did, inhibiting it (204). Dose was critical, since 5.0 mg/kg of morphine produced activation, but 0.5 mg/kg had no effect (258). With systemic injection, a low dose of morphine increased locomotion and a moderate dose decreased it (54). Hyperactivity occurred after 2.5 #g of/3-endorphin ICV, but catatonia resulted after 5 or 10 #g (9). The effects were greater at night (221) and in males (192,221), with an interaction between the two variables since the sex variable was more pronounced at night (221). Route of administration was also critical, with ICV morphine stimulating both horizontal and vertical activity, but IP morphine increasing only horizontal locomotion (291). Systemic injections of morphine and those into the caudate or ventral tegmental area produced hyperactivity, but those into the nucleus accumbens or reticular formation greatly decreased locomotion (54). When injected into the lateral hypothalamus, morphine or ~-endorphin decreased open-field behavior in a manner that was not reversed by naloxone or 6-OHDA, suggesting that the endogenous system may function independently of the dopamine system in influencing motor performance (443). As indicated above, the results were partly determined by which type of activity, either vertical or horizontal, was being measured, since various routes of administration of morphine differentially affected it. The enantiomers of U-50,488 also had differential effects on type of activity. The 1 form increased horizontal activity and did not affect vertical activity, but the d form left horizontal activity unchanged and inhibited vertical activity (101). DPDPE produced dose-dependent hyperactivity on both measures (291). Population differences were also noted in deer mice, with those from mainland populations reacting somewhat differently from those from island populations. Morphine at low doses stimulated activity but at high doses inhibited it in island deer mice, but all doses produced hyperactivity in mainland animals. For U-50,488, however, all doses decreased activity. Naloxone inhibited the effects of morphine in island but not mainland deer mice, and ICI 154,129 did the opposite. Naloxone or ICI 154,129 alone had no effect in mainland animals, but naloxone alone did decrease activity in island ones (192). Another withinspecies variable that influenced the effect of the opiates on activity was genetic obesity. Although low doses of FK 33-824 increased wheel running and produced linear running in both genetically obese and lean mice, a higher dose (100 ng ICV) produced opposite results, increasing running and not producing ataxia in obese, but producing ataxia and not altering running in lean ones (51). The marked differences in these populations might indicate differential opiate system activity in them. Confusion about the ability of antagonists to reverse the morphine-induced hyperactivity was found in other situations as well. Although naloxone reversed~the effect in some cases (219,313), it did not do so in others (443). ICI 154,129 was unable to reverse the effects of morphine or DPDPE (291). In deer mice, naloxone antagonized the increased locomotion produced by morphine at night but not during the daylight part of the diurnal cycle, and ICI 154,129 did the opposite (221). The increased activity level due to heroin was reversed by methyl-

OPIATES: 1987 naltrexone when microinjected into the nucleus accumbens but not into the periaqueductal gray (419). Chronic pretreatment with naltrexone potentiated the locomotor activation of morphine, although the effect lasted only one day after removal of the naltrexone pellet (24). Naloxone given alone to pregnant women near term increased the gross body movements of the fetuses, stimulated fetal breathing movements, and modified the distribution of behavioral states, with a prevalence of active sleep and active awake states as compared with quiet sleep. These findings suggest that the endogenous opiate system is involved in fetal activity (13). Naloxone suppressed the increased locomotion produced by the enkephalinase inhibitor acetorphan in mice and rats, as did 6-OHDA or a dopamine inhibitor, indicating that the hyperactivity of acetorphan might result from an interaction between enkephalins and the dopamine system (290). Naloxone had no effect on the locomotor-activating properties of dopamine injected directly into the nucleus accumbens in the rat but did disrupt amphetamine-induced locomotion (398). Species differences might be important here, since the antagonist did not affect amphetamine-stimulated locomotion in guinea pigs. Naloxone by itself had no effect on the behavior (10). In addition to altering locomotion in general, the opiate peptides have been implicated in the mediation of catatonic states and sedation. Morphine injected directly into the periventricular nucleus produced stuporous behavior, with erratic and disorganized movements (162). The kappa agonist PD 117302 at 7.5 and 10.0 mg/kg SC resulted in sedation for two to three hours in rats (178), and four other kappa agonists (bremazocine, tifluadom, ethylketazocine, and U-50,488) at analgesic doses resulted in marked stupor and muscle relaxation that was antagonized by WIN 44,441 (96). Catatonic states were seen after administration of 3-endorphin ICV in rats (9,343), DADLE intracisternally in dogs (156), morphine IP (343), ICV dynorphin and ethylketocyclazocine (54), and fentanyl IV in rats (207). Fentanyl also produced a loss of the righting reflex, and both effects were reversed by IV naloxone but not naltrexone methylbromide, indicating central control of that behavior (207). Catatonia still occurred after repeated applications of morphine and 3-endorphin, but it was weaker than with acute injections, and the overt immobility was accompanied by increased EMG amplitude both acute and chronic administration (343). Weinger (435) speculated that the "stiff-baby syndrome" characterized by general muscle rigidity, continuous EMG activity, and exaggerated startle might be related to a genetic defect that involves the endogenous opiate system since the symptoms are similar to opiate-induced catatonia. Opposite to catatonic reactions is the explosive motor behavior that results from microinjection of morphine directly into the periaqueductal gray of rats (203). Dynorphin into that structure, however, produced increased grooming (162). Morphine had a biphasic effect on grooming when peripherally administered, decreasing it in the first half hour and increasing it thereafter (81). Systemic naltrexone had no effect on either grooming or rearing in rats (172), and naloxone also did not alter rearing in rats (289). In mice morphine has a dose-dependent mydriatic effect which is antagonized by naloxone. The 1 but not the d isomers had that action, suggesting that the pupillary effects of opiates are mediated through specific opiate receptors (351). In opiate-dependent humans, neither naloxone nor morphine changed psychomotor performance (346). When Leu-enkephalin or one of four forms of dynorphin was microinjected into the substantia nigra of rats, contralat-

221 eral circling resulted that was not reversed by naloxone or WIN 44,443 (125). A quaternary but not tertiary form of naltrexone administered into the corpus callosum, zona incerta, or preoptic area produced rotational behavior, as well as backward locomotion, head swaying, and convulsions in rats (417). Apomorphine-induced turning and stereotypy were inhibited by morphine or enkephalin analogs when injected ICV or into the nucleus accumbens in rats (338), and the rotation was potentiated by MIF-1 systemically (84). The latter also reversed the direction of the circling in normal rats but did not in those with unilateral nigrostriatal lesions. The peptide had no effect on amphetamine-stimulated rotations, however (84). Thus, there appear to be a wide variety of motor behaviors mediated, at least in part, by the endogenous opiate system. There has been increasing interest in the possible opiate mediation of the effects of exercise. Many studies have reported that concentrations of immunoreactive 3-endorphin in plasma are elevated after strenuous exercise (90, 106, 142, 164, 168, 170, 241,303,353, 356, 427,428). Some have found that the concentrations rise during exercise (90, 106, 353,427,428), but others have reported that the concentrations remain unchanged during exercise and only increase after it has been completed (142, 168, 170). Still others measured 3-endorphin only before and after, so they could not make that distinction, although afterwards, it was elevated (79, 164, 241,303,356). The intensity of exercise was important, since at lower levels (up to 75% maximum capacity), 3-endorphin was unchanged (90, 106, 247, 356), but at higher intensity, the peptide rose (90,106). In horses, the endorphin increased after a two-furlong run and rose still more after five furlongs (164). Similarly, 3-endorphin was elevated during exhaustive graded or anaerobic treadmill exercise but not during submaximal running (353). A multiphasic 3-endorphin response was reported in one case, with an initial rise, then decrease, then a further decrease if the individual was working below capacity and a subsequent increase if the person was working hard (427). The elevation in plasma 3-endorphin after exercise was greater in trained athletes, as opposed to untrained ones (106, 303), and the trained individuals returned to baseline faster (164). Naloxone prolonged the elevation (164), and the rise was correlated with an increase in growth hormone and a decrease in insulin in untrained people (427). Since no significant mood changes were found after exercise, psychological state was not correlated with the rise in plasma 3-endorphin (142,168). There was no difference in the change in the peptide with age, when comparing young men (mean age of 26 years) and older men (mean age of 66 years) (168), and there was no difference between men with symptoms of coronary artery disease and those with a high probability of it. The increase in 3-endorphin was not due, therefore, to the presence or absence of pain during exercise (170). Individual differences were also reported, since in one study 12 of 15 women had an increase of 50-100% in 3-endorphin after exercise, but 3 had no change. Five other women had exceedingly high concentrations before exercise, and the concentration did not change afterward (356). Although no sex differences in the amount of 3-endorphin in plasma after exercise were found in one study (353), another reported some differential responses among men, amenorrheic, and eumenorrheic women. In all subjects the peptide increased with exhaustive exercise, but only in women did it also rise at only 66% maximum intensity. Exercise at 5°C prevented the increase in amenorrheic women but suppressed it in those who were normal. Rest at the cold temperature lowered the 3-endorphin in men and eumenorrheic women but had no effect in amenorrheic women. Thus, cold and sex hormones influenced

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the ~-endorphin response to exercise (428). There was, however, no difference in the amount of the rise of B-endorphin over days of a heat acclimation regime, in which exercise was undertaken on days 1, 4, and 8 of the 8 days of exposure to heat (241). Runners who collapsed near the end of two consecutive half marathon runs had higher concentrations of ~-endorphin in the plasma than did controls who finished the races. The control runners had elevated concentrations of the peptide after the exercise compared with the prerace measures. It was suggested that the unusually high ~-endorphin in the collapsed subjects was probably responsible for their insensitivity to pain, enabling them to keep going to exhaustion (79). This conclusion could be questioned if the peptide did not penetrate the blood brain barrier. It could be that there is also a concomitant increase in central concentrations of B-endorphin that is difficult to measure (421). The long-standing opposition to the concept that peptides can cross the blood-brain barrier, however, is rapidly disappearing. Other opiate peptides appeared to be unchanged after exercise. Plasma concentrations of Leu-enkephalin were unaltered regardless of the intensity of exercise, although the highest work load was 80°7o maximum (105). Neither Met-enkephalin (241,303), nor Peptide F (preproenkephalin 107-140) (241) was influenced by exercise. Naloxone increased the subjectively experienced level of exhaustion after exercise, as measured on a rating scale, suggesting that endogenous opiates might be involved in this response (42). The antagonist also decreased the number of exercise events cats would perform per day (431), further suggesting a role for the opiate system in fatigue after exercise. Such effects were not mediated by catecholaminergic responses, since naloxone did not affect the concentrations of plasma norepinephrine and dopamine during exercise. Apparently, the opiate system is involved in the effects of strenuous activity that occurs during exercise, and 13-endorphin seems to be the most likely candidate to mediate those actions. SEX, PREGNANCY, AND DEVELOPMENT

As in past years, in 1987 interest still remained in the possible role of the endogenous opiate system in the regulation of sexual behavior in males and females. In humans of both sexes, chronic administration of morphine, heroin, methadone, fl-endorphin, or DAME produced a naloxone-reversible inhibition of sexual activity. Although equivocal results occurred after administration of opiate antagonists, they suggested that an increase in the endogenous opiate peptides inhibits or disrupts copulatory behavior, perhaps through a modulation of monoamine neurotransmitters or of the release of GnRH (330). It appeared that the kappa receptors were particularly important in mediating the sexual response in male newts (Taricha granulosa). Bremazocine and ethylketocyclazocine, but not morphine, suppressed sexual behavior. The effect of bremazocine was naloxone reversible, but naloxone alone had no effect in those sexually inactive before treatment, suggesting opiate mechanisms may not normally exert a tonic inhibition of amphibian sexual behavior (88). In rats, however, naloxone microinjected into the medial preoptic area produced a dose-related impairment of the copulatory rate in normal males (21). In intact rats that had ejaculated repeatedly with one female until satiation, naloxone inhibited the resumption of mating after the reintroduction of the female partner. The antagonist suppressed mounting and ejaculation in rats 14 but not 7 days after castration, suggesting that naloxone might have attenuated the

reward associated with sex in castrated and sex-satiated rats. In support of that hypothesis, in a conditioned place preference for the compartment in which the male had copulated with a female rat, naloxone and/or castration reduced the amount of time the male spent in that compartment (294). Ejaculation in rats seems to activate an opiate mechanism since it decreased sensitivity to painful and sexual stimuli in them, although it enhanced those responses after the postejaculatory refractory period. Naloxone reversed the pain suppression but had little effect on sexual behavior. Plasma ~-endorphin was unaffected by ejaculation, and the injection of the peptide did not alter display of sex or response to pain, suggesting that the mechanism does not involve the endorphin (116). Similarly, in female rats ~-endorphin injected SC, ICV, or into the periaqueductal central gray did not alter sexual behavior, nor did plasma ~-endorphin concentrations change after sexual interactions. Naloxone, however, did reverse the suppression of sexual receptivity in females after ejaculation by males, indicating an opiate but not ~-endorphin mechanism (114). Further supporting that notion was the finding that naloxone also stimulated sexual behavior that was inhibited by stimulation of the uterine cervix or by lactation, without any alteration of ~-endorphin concentrations (115). The opiate peptide that might be involved is Met-enkephalin. Although injection of it or Leu-enkephalin had no effect on sexual activity in female rats, a combination of the former with kelatorphan, an enkephalinase inhibitor, suppressed sex (32). The actions of leumorphin, a recently characterized endogenous opiate peptide, produced the opposite action, facilitating the lordosis reflex in females. The effect was long lasting but could be interrupted by midbrain infusion of an antiserum to prolactin, suggesting a possible interaction for it (371). It appears that specific activation of receptor subtypes differentially affects lordosis behavior, since delta-receptor peptide stimulated the response at all doses, dynorphin 1-9 had no significant effect, and both ~-endorphin and morphiceptin had dose-dependent biphasic effects, suppressing at low doses and facilitating at higher ones (329). Although ~-endorphin may not mediate sexual behavior, secretions of it are influenced by gonadal steroids, since in ovariectomized pigs, progesterone, estradiol, or a combination of the two greatly increased concentrations of the peptide in uterine secretions. Pseudopregnancy induced by injection of estradiol valerate also raised the ~-endorphin immunoreactivity in the uterine secretions (259). Further support for this notion comes from a report of alteration of the endogenous system in the preoptic area of rats by gonadal steroids. The concentration and binding of the peptide were highest during pregnancy, lowest during lactation, and at intermediate levels after ovariectomy. In ovariectomized rats treated with estrogen and progesterone, the concentrations were similar to those during pregnancy (163). In pregnant women the concentration of ~-endorphin is elevated, with higher concentrations in the amniotic fluid during the second trimester than at term. At cesarean delivery, those who had started labor had lower concentrations than those without labor, perhaps supporting a notion of opiate mediation of parturition. High local concentrations would promote uterine relaxation, appropriate for the early stages of pregnancy, and lower concentrations at term would promote contractions, as appropriate for delivery (233). The concentration of ~-endorphin in placental tissue was higher than in maternal or cord plasma, and there was no effect of gestational age or type of delivery (cesarean or vaginal) on the peptide concentration (246). There was no difference in ~-endorphin immunoreactiv-

OPIATES: 1987 ity in umbilical venous blood at birth for those women who received a warm tub bath to promote relaxation during the first stage of labor, nor was there any benefit to the neonate at birth (147), indicating further that the peptide probably does not mediate the stress of birth but rather other mechanisms such as uterine contractility. Other opiate peptides might be involved in the birth process. Disruption of parturition by moving the pregnant rat to another chamber after the birth of the second or third pup increased the time course of parturition, but naloxone at the time of transfer reversed that inhibition of the birth process. Since those that received naloxone had higher concentrations of oxytocin, the stress of moving might have activated opiate pathways that inhibited oxytocin release (255). Naloxone given just before cutting the cord increased the plasma concentrations of norepinephrine and epinephrine, indicating that opiate blockade from birth markedly augments neonatal sympathoadrenal response in the term newborn lamb (325). Pregnant rats had an elevated threshold for reflexive jumping to footshock, and the administration of naltrexone IT reduced it. In nonpregnant rats or if given systemically, the antagonist had no effect, suggesting that the analgesia of gestation is mediated by spinal opiate receptors (137). Hypophysectomy did not affect the higher threshold in pregnant rats, despite the fact that it did lower the plasma concentration of stress-induced B-endorphin. The pituitary, thus, did not play a role in opiate analgesia during pregnancy (25). With prenatal exposure to opiates, birth causes withdrawal within a few days, including hyperactivity, irritability, convulsions, and crying. There is high arousal, muscular hypertonia, and difficulty in orienting and maintaining alertness. The infants are unresponsive to maternal comforting, and all these effects may persist through toddlerhood. Methadone has the same effects, but it is transitory (61). Rats exposed to morphine during fetal life and lactation had hyperinnervation by Met-enkephalin neurons in the nucleus caudatus, cortex, and pons-medulla oblongata. At birth, the concentration of the peptide was higher than normal, and the difference was magnified with growth. Thus the endogenous opiate system seems to be implicated in the natural trophic regulation of the growth and development of the CNS (89). Continuous blockade of receptors by naltrexone from birth for ten days increased neuronal maturation in the rat brain. Lengths of dentrites and concentrations of spines in them in the pyramidal cells in the cortex and basilar dendrites of the hippocampus were increased, as were lengths of branches of Purkinje neurons and concentrations of spines in granule cells of the dentate gyrus (169). Blockade of receptors with high doses of naltrexone for six days stimulated proliferation of developing cerebellar cells, but low doses inhibited it, as did Met-enkephalin (452), further supporting the notion that the endogenous opiate system can regulate the development of the nervous system. The use of selective radioligand binding with quantitative autoradiography to examine the ontogeny of mu, kappa, and delta receptors in the developing rat brain showed affinities to all three to be similar in the neonate and the adult. Mu and kappa receptors appeared early, with the delta ones coming much later, especially in the basal forebrain. The densities of the kappa receptors remained constant throughout development, but there was a transient appearance or redistribution of mu receptors in several brain areas. Delta binding increased markedly in the three postnatal weeks in all areas examined, suggesting that early development was probably mediated by the kappa and mu receptors (238).

223 The development of the B-endorphin pituitary system is affected by prenatal ethanol. Rats fed ethanol from the first day of pregnancy to parturition gave birth to pups with higher than normal/3-endorphin concentrations in the pituitary on day 5 but lower than normal concentrations on days 8, 14, and 22. An isocaloric sucrose diet produced similar but weaker effects (134). Neonatal gonadal steroid treatment, with males being administered testosterone and females estrogen, decreased the concentration of B-endorphin in the neurointermediate lobe of the pituitary in adulthood in both sexes, with the elevation greater in females. It had no effect on the concentration in the anterior pituitary of males but increased it in females, and no effect in either sex in the hypothalamus. Thus, gonadal steroids influence the development of the pituitary B-endorphin system (113). The opiate system may mediate the response to maternal deprivation. It may be responsible for the comfortable feelings associated with maternal affection and postprandial contentment (229). Central but not circulating B-endorphin mimics the biochemical and physiological alterations elicited by maternal deprivation, especially a decrease in ornithine decarboxylase (ODC) activity, an index of cell growth and differentiation. It only acts this way in the first two weeks of postnatal age and appears to occur independently of the pituitary. It blocks the effects of exogenously administered growth hormone and insulin (373). Posttranslational acetylation of B-endorphin at the N terminus affects its ability to alter ODC activity. Intracisternal administration of it increased brain ODC in 6- and 9-dayold rats but not in 25-day-old rats or adults and had no effect on ODC in peripheral tissues. Systemic injection increased ODC in the heart, liver, and brain, suggesting that the peptide was probably related to normal development in mammalian tissues (29). There were no age-related alterations in diurnal cycles of concentrations of plasma •-endorphin, with young men (1821 years) and older ones (55-62 years) having the same morning rise in it (112). There were also no differences in young and old rats in their endocrinological response to naloxone, with serum LH increasing, prolactin decreasing, and FSH remaining unchanged at both ages (279). Continuous blockade of the opiate system with naltrexone for up to four weeks in prepubertal boys had no effect on FSH or LH concentrations in the plasma, indicating no support for opiate mediation of the onset of puberty in human males (244). Some alterations of the opiate system have been noted with aging. Although the mean 24-hour concentration of B-endorphin in the plasma did not change with age, the circadian rhythm seen in young men (28-37 years) was absent in old ones (78-84 years). In the elderly, the correlation between the peptides and ACTH and cortisol that was evident earlier disappeared (366). In both men and women, there was no change in plasma concentrations of Met-enkephalin with age (299). There have been contradictory reports of increases or decreases in opiate content in various regions of the brain in mammals. There was, however, a general decrease in receptor densities with no change in affinity in different areas in both mammals and invertebrates, and in the latter there was an increase in concentration of Met-enkephalin. The significance of these changes is still unclear, but they are long-term, not rapid (256). More specifically, the number of mu receptors in the whole brain of 15- and 22-month-old rats and in the hypothalamus of 22-month-old rats was significantly lower than in the same tissues in young ones (2 months). Since administration of testosterone did not modify the number of hypothalamic receptors, the decline with age is not related to gonadal

224

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steroid decrease (336). Here, too, the significance of the finding remains to be discovered. I M M U N O L O G Y A N D CANCER

In 1987 there was continued interest in the possible interaction between the immune and opiate systems. One line of support comes from studies of the properties of interferon, which is used in treatment of some disorders of the immune system. Interferon produced a naloxone-reversible increase in the firing rate of neurons from the ventromedial hypothalamus and a decrease in those from the preoptic and anterior hypothalamus. The drug might, therefore, exert its effect through opiate receptors in the hypothalamus (312). As mentioned previously, interferon has also been shown to attenuate the severity of naloxone-precipitated withdrawal from morphine (78, 93, 251), suggesting that the immune system may modulate the function of the CNS. Muramyl dipeptides (MDP), which have a variety of immune modulatory and neuropharmacologic effects, also decreased the severity of naloxone-precipitated withdrawal in rats and attenuated morphine-induced antinociception. Chronic morphine, furthermore, altered MDP-induced fever, supporting the notion of an interaction between the immune and opiate systems (92). In cancer patients, FK 33-824 did not alter endocrinological function, but in normal individuals and noncancer patients, the enkephalin analog increased secretion of prolactin and growth hormone and decreased release of LH, cortisol, and /3-endorphin, suggesting a change in the function of the endogenous opiate system in cancer patients (266). The dose-response of natural killer ceils in isolated blood lymphocytes from cancer patients was also different from that from normal volunteers. In both, Leu-enkephalin was more potent than Metenkephalin in activating the natural killer cells, but the effector:target ratios varied for cancer patients and controls (104). DADLE decreased the duration and amplitude of the action potential in neuroblastoma cells, and naloxone blocked the action but did not have any effect itself, further indicating modification of immune system responses by the opiate peptides (85). Proliferation of autologous mixed lymphocyte reaction was augmented by physiologic concentrations of/3-endorphin, but the peptide had no effect on allogenic mixed lymphocyte reaction, and a-endorphin was ineffective on both. Naloxone partially antagonized the augmentation by/3-endorphin (126). Morphine had immunosuppressive effects, decreasing resistance to cancer and microbial pathogens in most cases (446). Naloxone in vitro inhibited proliferation of human ovarian cancer cells, and in vivo retarded growth of the cancer tumors inoculated in mice when given as a pretreatment or after inoculation and increased survival time (228). Intermittent blockade of the opiate receptors by a small dose of naltrexone (0.1 mg/kg) delayed onset and growth of tumor cells in mice inoculated with neuroblastoma ceils, prolonging survival time (278, 311,453,454), and complete blockade with a large dose of naltrexone (10.0 mg/kg) accelerated onset and growth of tumors and death (278, 31 I, 453). Both doses elevated amounts of/3endorphin and Met-enkephalin in the tumor tissues (278, 311, 453, 454) and increased the density of DADLE and ethylketocyclazocine binding sites while having no effect on affinity (278,311). In a variety of malignant and benign tumors of ectodermal, mesodermal, and endodermal origin in many different species, the presence of/3-endorphin and Met-enkephalin was found by radioimmunoassay, and both Met- and Leu-enkephalin were detected in tumor tissue by immunocytochemistry, indicating endogenous opiates might be fundamental features of human and animal tumors (455).

O T H E R BEHAVIORS

Both aggression and defensive behavior appear to be mediated, at least in part, by the endogenous opiate system. Microinjection of DAME into the bed nucleus of stria terminalis, an area rich in enkephalin-containing cells and fibers, facilitated attack and defensive behavior in the cat. When put directly into the nucleus accumbens, DAME inhibited defensive behavior, but had no effect in the caudate nucleus. Naloxone placed into the nucleus accumbens facilitated defense (48). Defensive behavior was also elicited by electrical stimulation of the periaqueductal gray of cats, and DAME into that structure raised the response threshold for electrical stimulation. Naloxone reversed the suppression by DAME (379). Electrical stimulation of the ventromedial hypothalamus produced attack in cats, and when the central gray was stimulated simultaneously, potentiation occurred at ventral sites and inhibition at dorsal sites of the central gray. The aggression was also suppressed by D-Ala2-Met-enkephalin into the central gray, suggesting opiate mediation of the response (342). Stimulation of the lateral hypothalamus induced quiet biting attack, and dual stimulation of it and the periaqueductal gray resulted in attack inhibition at mostly dorsal sites and facilitation at mostly rostral ones. Naloxone blocked the action at most but not all of the sites, indicating involvement of the opiate system in this aggressive response (434). Defeat shifted the dose-response curve for morphine-induced analgesia to the right, but had no effect on morphine's suppression of schedule-controlled behavior. Defeat alone produced analgesia and inhibited fixed ratio responding, and naltrexone antagonized these effects and those produced by morphine. In the attackers, there was no alteration of the action of morphine, and attack alone had no effect on pain or responding. Thus, defeat but not attack alters the endogenous opiate system (292). In subordinate mice in the resident-intruder paradigm, analgesia and stimulation of feeding and activity level occurred, indicating activation of the opiate system in these animals. If the mice had previously been housed in groups, there was no fighting, so the encounters between resident and intruder did not produce opiate activity (405). Both defeat-induced analgesia of intruders and aggressive behavior by residents were modulated by calcium channel agonists and antagonists, with the former inhibiting the behaviors and the latter promoting them, suggesting that the calcium channel agents might interact with the opiate system (215). Another behavior that may be mediated by the opiate system is hibernation, although interest in it dwindled somewhat in 1987. Hibernation-induction trigger (HIT) is an endogenous plasma factor isolated from winter hibernating animals. This factor depressed the electrically-induced contractions of the guinea-pig ileum in a manner similar to that of morphine, but the inhibition was not naloxone reversible, suggesting that HIT is not working directly on the opiate receptors (47,320, 395). In summer-active ground squirrels, HIT induced hibernation that was partially blocked by naloxone pretreatment, and when the naloxone pellet was removed, the animals hibernated just as frequently as controls with HIT (47,395). Unexpectedly, the kappa opiate agonist U69593 also antagonized HIT-induced hibernation, and the agonist had no effect alone (320,395). Thus, HIT may not have opiate properties itself, but may induce hibernation as a potent precursor or releaser of opiate peptides (395). During hibernation, the Columbian ground squirrel exhibited an attenuated thermal response to morphine, with hyperthermia resulting from both high and low doses. In nonhibernating ones,

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225

high doses of morphine produced hypothermia and a suppression of metabolic rate. Naloxone pretreatment inhibited or reversed both the hyperthermia and hypothermia induced by morphine, and a decrease in ambient temperature to 5°C enhanced the hypothermia and attenuated the hyperthermia. The reduction in morphine efficiency in hibernation was suggestive of increased endogenous opiate activity that may occur with the beginning of hibernation (433). There are also pronounced seasonal cycles of ~3-endorphin in the plasma not related to hibernation, as noted in rams living outside, with low concentrations in spring and early summer and the highest concentrations in late summer and fall. In those living indoors with artificial photoperiods alternating 1216 weeks of long days (16 hours of light) and short days (8 hours of light), there were corresponding changes, with transfer from long days to short raising the concentrations of ~-endorphin and the reverse switch lowering them. There was a decrease of the peptide in the pituitary associated with the increases in the blood (99). Exposure to noise suppressed the Metenkephalin content in the guinea-pig cochlea, with increasing intensities producing greater decreases. Enkephalin, therefore, is an olivocochlear neuroactive substance, even at moderate intensities (103). A possible role for ~-endorphin in limb regeneration and wound healing was postulated, since vertebrates with regeneration capability have a higher concentration of the peptide in plasma than those species with limited or no regeneration. Lower concentrations may imply a lower pain threshold and need for promotion of faster healing with formation of scar tissue that blocks regeneration in mammals and other nonregenerating vertebrates (425). Diabetes may also be mediated by the opiate system, since there were changes in Met-enkephalin content in diabetic rats repeatedly exposed to streptozotocin-induced pain. There was an elevation of the enkephalin in the spinal cord and plasma and a lowering of it in the pituitary, adrenal medulla, and pancreas. The gradual increase in the pain threshold over 6-7 weeks was completely reversed by insulin or by naltrexone, suggesting possible opiate mediation (234).

Exposure of the adult male rat to magnetic resonance imaging (MRI) has been shown to abolish nocturnal antinociceptive responses to morphine. If there is generalizability of the finding across species, MR1 exposure in humans may have clinically relevant effects on actions of analgesics like morphine (345). Also of practical significance might be the comparison of the bioavailability of naloxone and naltrexone given orally or buccally. The latter involved applying it between the cheek and lower gum without allowing swallowing of it. Both antagonists had been known to undergo extensive first-pass metabolism after oral dosing, and that finding was supported here. Less than 1%0 of either was bioavailable in the plasma after oral administration, as compared with about 70% after buccal administration. The latter was equivalent to that after IV injection (185). Chronic administration of naloxone for nine days raised the concentrations of Met-enkephalin in both lobes of the pituitary, up to 90% above control concentrations. This finding suggests that an opiate receptor mechanism may play a role in the content of the peptide in the pituitary, although treatment with FK 33-824 had no effect on it (133). The purported endogenous antagonist FMRFamide was found in the ventral neurons of the buccal ganglia and muscles of Aplysia along with two other neuropeptides that have cardioactive properties. The FMRFamide, however, had opposite responses. The physiological role of the peptide was unclear, with the possibility of modulation of the buccal muscles (267). It is typical of much of the research on the opiate peptides that their physiological role has not yet been determined despite the fact that we know something about the behaviors produced by their pharmacological administration. ACKNOWLEDGEMENTS This work was sponsored in part by the Edward G. Schlieder Educational Foundation and the Veterans Administration.

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