The link between analgesia and cardiovascular function: roles for GABA and endogenous opioids

Progress in Neurobiology Vol. 19, pp. 1 to 17, 1982 Printed in Great Britain. All rights reserved

0301-0082/82/020001-17508.50/0 Copyright © 1982 Pergamon Press Ltd

THE LINK BETWEEN ANALGESIA AND CARDIOVASCULAR F U N C T I O N : ROLES FOR GABA AND E N D O G E N O U S OPIOIDS F. V. DEFEUDIS Ddpartement de Biologie, U.P.S.A., 128 rue Danton, B.P. 325, 92506 Rueil-Malmaison Cedex,

France (Received 8 March 1982)

Contents I. Introduction 2. GABAand cardiovascular function 2.1. Actionsof GABA-ergicagents on cardiovascular function 2.2. The GABA system of blood and blood vessels 2.3. GABA-ergicmechanisms and human cardiovascular disorders 3. Endogenousopioids and cardiovascular function 4. GABA and analgesic mechanisms 4.1. Introduction 4.2. Effectsof opiates on central GABA-ergicsystems 4.3. Effectsof GABA-ergicagents on analgesia produced by opiates or opioid peptides 4.4. Analgesia induced by GABA-agonists,GABA-Tinhibitors or GABA uptake inhibitors 4.5. Comment on GABA-ergicanalgesia 5. Endogenousopioids and analgesia 6. Relationship between GABA and endogenous opioids in analgesia; some effects of benzodiazepines 7. Benzodiazepinesand cardiovascular function 8. Baclofen--Aderivative of GABA with analgesic and cardiovascular actions 9. Concluding remarks References

1 1 1 3 3 4 5 5 5 6 6 7 7 8 8 9 10 11

1. Introduction With increasing emphasis being placed on studies of the roles that 7-aminobutyric acid (GABA) might play in the regulation of physiological mechanisms and behavior (see, e.g., Roberts et al., 1976; Krogsgaard-Larsen et al., 1979; Mandel and DeFeudis, 1979; DeFeudis and Mandel, 1981; Okada and Roberts, 1982), and with the added information gained from studies of the recently-discovered endogenous opioids (see, e.g., Hughes et al., 1975; Kosterlitz, 1976; Lord et al., 1977; Costa and Trabucchi, 1978, 1980; Olson et al., 1981), it is becoming evident that mechanisms controlling cardiovascular function and analgesia are interrelated. Even though GABA and endogenous opioids are not the only substances involved in this proposed liaison, an analysis based on these substances might help to further define analgesia and cardiovascular mechanisms, as well as providing a rationale for further studies. The importance of such an analysis in relation to drug therapy is obvious.

2. G A B A and Cardiovascular Function 2.1.

A C T I O N S OF

GABA-ERGIC A G E N T S

ON C A R D I O V A S C U L A R F U N C T I O N

It has long been known that administration of GABA can affect the mammalian cardiovascular system (Takahashi et al., 1955, 1958; Romanowski et al., 1957; Romanowski, 1959; Elliott and Hobbiger, 1959; Bhargava et al., 1964). GABA appears to decrease 1 J,P.N. 19 1;2 A

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arterial pressure and heart rate by a central action that reduces sympathetic outflow from the medullary area (see e.g., DeFeudis, 1981a), but a peripheral mechanism could also be involved (Elliott and Hobbiger, 1959). Muscimol and other potent GABA-agonists (e.g., 3-aminopropanesulfonic acid, kojic amine), administered intracerebroventricularly (i.c.v.), have also been shown to decrease blood pressure and heart rate and to inhibit renal sympathetic nervous discharge in anaesthetized cats, and such effects were reversed by bicuculline or picrotoxin, but not by strychnine or physostigmine (Antonaccio and Taylor, 1977; Antonaccio et al., 1978a, b; Sweet et al., 1979~ Snyder and Antonaccio, 1980; Bousquet et al., 1981). Pressor responses produced by electrical diencephalic stimulation in chloralose-anaesthetized cats were also reversed by i.c.v.-administered GABA or muscimol (Antonaccio et al., 1978a). In addition, GABA-agonists might attenuate the baroreceptor reflex in the cat by a central action (Sweet et al., 1979). Recent experiments in which either the cisterna magna or spinal cord of the anaesthetized cat was perfused with muscimol-containing solution indicated that muscimol might lower blood pressure and heart rate by acting in the cisterna maqna (hindbrain) region (Williford et al., 1980b). lntracisternally-administered GABA to ether-anaesthetized rats (Sgaragli and Pavan, 1972) and intravenously-administered GABA (1 5 ~g) to pentobarbitone-anaesthetized rats (Horvath et al., 1980) also produced depressor responses. Other GABA-agonists, such as 4,5,6,7-tetrahydroisoxazolo-[5,4-c]pyridin-3-ol (THIP) (given i.c.v.), isoguvacine propyl ester, and isoarecaidine propyl ester (both given i.v. or i.a.) also decreased blood pressure and heart rate in chlorolose-anaesthetized cats by effects that appeared to involve activation of central GABA-receptors (Snyder et al., 1980; Porsius et al., 1981). In pentobarbitone-anaesthetized dogs~ GABA (i.c.v.) produced hypotension that could be reduced by pretreatment with cocaine (1 mg/kg, i.c.v.), and reversed to a hypertensive response by pretreatment with reserpine (0.3 mg/kg, i.m.), results which indicated that the hypotensive action of GABA might be related to a release of norepinephrine (NE) (Dhumal et al., 1980; see also Yessaian et al., 1969; Horvath et al., 1980). The stimulant effect of angiotensin II on cardiac sympathetic ganglia in spinal dogs (recorded as an increase in heart rate) was antagonized by intra-arterially-administered GABA (50 or 500/tg) or muscimol (50 or 100#g), and this effect of GABA (5011g) was antagonized by intra-arterially-administered picrotoxin (2 rag) (Furukawa and Kushiku, 1981; see also Kimura et al., 1977). It is also well known that systemic or intracerebral injection of picrotoxin (an agent that blocks GABA-associated C1 -ionophores; see e.g., Ticku, 1977) also produces cardiovascular effects in mammals (e.g., Bircher et al., 1965; Share and Melville, 1965; Polosa et al., 1972; Lee et al., 1972; DiMicco et al., 1977a, b). Intra-arterial injection of picrotoxin or bicuculline produced decreases in blood pressure and heart rate by actions that were reversed by muscimol (DiMicco et al., 1977b; DiMicco and Gillis, 1979). Thus, DiMicco et al. (1979) suggested that although GABA-agonist-induced bradycardia appears to be caused by an inhibition of central sympathetic outflow (see above), GABAantagonist-induced bradycardia is probably caused by stimulation of parasympathetic function and mediated by the vagal nerves. GABA-receptors that influence sympathetic cardiovascular activity appear to be located in the forebrain (e.g., Antonaccio and Taylor, 1977), whereas those that influence parasympathetic cardiac function are located in the brain stem (e.g., DiMicco et al., 1977b; DiMicco and Gillis, 1979). Bicuculline-methiodide, injected directly into the nucleus ambiguus, but not in other brain stem nuclei, caused marked decreases in blood pressure and heart rate which were mediated by the vagus nerve, and these effects were reversed by muscimol; thus, the nucleus ambiguus might be the site of a GABA-receptor-mediated inhibition of vagal outflow (DiMicco et al., 1979). Administration of bicuculline (5 and 25/~g) into the lateral ventricle of vagotomized cats (and restricted to forebrain areas by cannulating the aqueduct of Sylvius) elicited dose-related increases in arterial pressure and heart rate (DiMicco and Gillis, 1979; see also Williford et al., 1980a). Administration of muscimol into the lateral or third ventricle did not alter blood pressure or heart rate, but did reverse the cardiovascular effects of bicuculline (Williford et al., 1980a). Thus, tonically-

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active GABA-ergic systems might be involved in regulating central autonomic outflow to the cardiovascular system. Anaesthetized animals were used in many of the studies discussed above. Therefore, interpretation of the results obtained in terms of GABA-ergic mechanisms requires some caution, since certain general anaesthetics (e.g., ~-chloralose, pentobarbitone) might mimic or enhance the central actions of GABA (e.g., Schmidt, 1964; Nicoll, 1975; Brown and Constanti, 1978; MacDonald and Barker, 1978, Lalley, 1980b). 2.2. THE G A B A SYSTEM OF BLOOD AND BLOOD VESSELS

Extra-cerebral and/or cerebrovascular GABA-ergic mechanisms might also be involved in cardiovascular regulation. Whole blood of various mammals contains about 0.5-1.3 ~tM GABA, and acute administration of GABA-~-oxoglutarate transaminase (GABA-T) inhibitors to rats produces increases in both brain and blood GABA contents (Ferkany et al., 1978, 1979). GABA-T activity is present in cerebral blood vessels (e.g., van Gelder, 1965) and in blood platelets of mammals (White, 1979). Blood-borne GABA might regulate synaptic transmission in sympathetic ganglia by decreasing the release of excitatory transmitter (Kato et al., 1980). Fujiwara and co-workers (1975) first showed that GABA-receptors are present in cerebral arteries. GABA (10-7-10 -5 M) relaxed strips of basilar and middle cerebral arteries of the dog; this action of GABA was more pronounced in the presence of active tension (5-hydroxytryptamine (5-HT), l0 -8 M), and was antagonized by pretreatment with picrotoxin (10 5 M). As GABA did not produce relaxation of dog or rabbit aorta, mesenteric artery or portal vein, and as glycine or glutamate (10-8-10-5 M) did not relax cerebral arteries, this action of GABA was considered to be selective. Various GABAagonists relaxed cerebral arteries with relative potencies that were consistent with their effects on GABA-receptors of mammalian central neurones; the ECso for GABA was 8 × 10-TM and that of muscimol was 3.8 × 10-TM for vasodilatation of cat middle cerebral arteries (Edvinsson and Krause, 1979). GABA also dilated rabbit isolated basilar artery (previously contracted with 5-HT) with an EC5o -~ 2.4 × 10-5 M, and pretreatments with bicuculline (3 x 10 -~ and 3 x 1 0 - 6 M) or picrotoxin (10-7-10 -6 M) inhibited this response; baclofen was inactive, and 3-aminopropanesulfonic acid was less active than GABA (Anwar and Mason, 1982). Such cerebrovascular GABA-receptors might be involved in mediating the increases in cerebral blood flow and brain tissue oxygen tension that have been produced by administration of GABA or muscimol in mammals (Mirzoyan and Akopyan, 1967; Edvinsson et al. 1980). Ligand-binding studies have also indicated that GABA-receptors are present in cerebral blood vessels. [3H]Muscimol was bound to bovine pia-arachnoid membranes by a high-affinity (K~ -~ 4 x 10 -8 M) process that was inhibited by GABA-agonists and by bicuculline with relative potencies that were similar to those found for GABA-receptors of mammalian brain (Krause et al., 1980). Also, in accord with results obtained with brain binding assays, d-7-amino-fl-hydroxybutyrate (d-GABOB) was more potent than /-GABOB in displacing [3H]muscimol from cerebrovascular GABA-receptors (Roberts et al., 1981). 2.3. GABA-ERGIC MECHANISMS AND HUMAN CARDIOVASCULAR DISORDERS GABA-receptors of blood vessels might be involved in human disorders such as hypertension, migraine and atherosclerosis. In this regard, it seems noteworthy that GABA is one of the active principles of the crude drug "sh~riku" (extracted from the roots of the plant Phytolacca esculenta) which is used as a diuretic in oriental medicine and which also decreases blood pressure (Funayama and Hikino, 1979). Increases in GABA levels of the cerebrospinal fluid were found in patients with thromboembolic cerebrovascular disease or during migraine attacks (Welch et al., 1976). Recent clinical studies have also revealed that oral administration of GABA for 8 weeks is an effective treatment for

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cerebrovascular disorders, especially cerebral arteriosclerosis (Otomo et al., 1981). In thiy, latter study, GABA administration also produced improvement of the psychological symptoms that accompany cerebral infarction and cerebral haemorrhage. The significance of this finding becomes clearer when one considers the coupling that exists between GABA- and benzodiazepine-receptors (e.g., Costa et al., 1976: Tallman et al., 1980k and the studies which have revealed that a single dose of diazepam (10mg/kg, s.c.) can decrease cerebral GABA content in rats (Semiginovsky el al., 1976), and that diet-induced atherosclerosis in rabbits can be reduced if animals are given daily doses of diazepam (Nerem, 1979). Thus, diazepam, by reducing anxiety (via a facilitatory action on central GABA-ergic function) might be of value for treating certain cardiovascular disorders in man (see Section 7). 3. Endogenous Opioids and Cardiovascular Function Mechanisms controlling blood pressure and pain sensitivity are interrelated. Humans with essential hypertension have increased pain thresholds (Zamir and Shuber, 1980), and rats with experimentally-induced renal hypertension, desoxycorticosterone acetate (DOCA) salt-induced hypertension and genetic hypertension also exhibit hypoalgesia (Zamir and Segal, 1979; Zamir et al., 1980; Saavedra, 1981: Randich and Maixner. 1981). Since naloxone reverses this hypoalgesia, endogenous opioid systems appear to be involved. In support of this idea, renal-hypertensive and spontaneously-hypertensive rats (SHRs) have increased opioid activity in the spinal cord which might explain their decreased sensitivity to pain (Zamir et al., 1980), and SHRs have decreased enkephalm content in their peripheral organs which might reflect an increased turnover of endogenous opiates (DiGiulio et al., 1979). Administration of endorphinomimetic substances has been shown to reduce blood pressure and heart rate in several mammalian species (e.g., Feldberg and Wei, 1977: Florez and Mediavilla, 1977; Lemaire et al., 1978; Moore and Dowling, 1980), and fl-endorphin might decrease heart rate in depressed human subjects (Angst et al., 1979: Catlin et al., 1980). Hypotension produced by certain physiological stresses can be reduced by naloxone, which could act by antagonizing the effects of those endogenous opioids that are released by stress (Dashwood and Feldberg, 1980). It is also of interest that the corticotropin-releasing factor stimulates fl-endorphin secretion both in ritro and in vivo and lowers blood pressure when given intravenously (Vale, 1982). Endogenous opioids also appear to be involved in the centrally-mediated hypotensive effect of the ~2-adrenoceptor-agonist clonidine (Farsang and Kunos, 1979; Kunos et al., 1981) and clonidine is known to produce analgesia in laboratory animals (e.g., Fielding and Lal. 1981). Clonidine-induced analgesia (like GABA-related analgesia, see below)is not antagonized by naloxone. Randich and Maixner (1981) found that both SHRs and renal-hypertensive Wistar Kyoto rats (WKYs) showed significantly longer latencies than normotensive WKYs in their responses to thermal stimulation (hot-plate assay), and Saavedra (1981) found that SHRs were less responsive to a thermal stimulus (tail-flick test) than normotens~ve WKYs. In the latter study, pretreatments with naloxone or (-)-propranolol increased pain sensitivity in SHRs, but not in WKYs, indicating that both endogenous opioids and catecholamines might be altered in the CNS of SHRs. It is also noteworthy that food restriction reduces the blood pressure of the SHR (Wright et al., 1981) as well as reducing pain sensitivity in normal rats by a naloxone-sensitive mechanism (McGivern and Berntson, 1980). Weight loss after hypertension had become well established, also caused a decrease in blood pressure, and this effect was more pronounced in the SHR than in the normotensive WKY rat (Wright et al., 1981). In this regard, it should be recalled that both the GABA system and endogenous opioid systems appear to be involved in controlling ingestive behavior (e.g., Morley, 1980; DeFeudis, 1981b; Sanger, 1981; Jalowiec et al., 1981; Olson et al., 1981), and that hypoalgesia produced by food deprivation is reversed by naloxone (McGivern and Berntson, 1980).

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4. GABA and Analgesic Mechanisms 4.1. INTRODUCTION GABA-ergic mechanisms appear to be involved in opiate, ethanol and barbiturate actions and tolerance in mammals, including man (see e.g., Krogsgaard-Larsen et al., 1979; Mandel and DeFeudis, 1979; DeFeudis and Orensanz-Mufioz, 1980; DeFeudis and Mandel, 1981 ; Okada and Roberts, 1982). Regarding the actions of opiate analgesics (e.g., morphine) and their antagonists (e.g., naloxone), several neurotransmitter systems other than the GABA-ergic system have also been implicated (e.g., acetylcholine (ACh), NE, dopamine (DA), 5-HT; see, e.g., Tenen, 1968; Harris, 1970; Burks and Dafny, 1977; Pollard et al., 1977; Sugrue, 1979; Brase, 1979; Snelgar and Vogt, 1981). Of course, endogenous opioid peptides (e.g., Hughes et al., 1975; Kosterlitz, 1976) serve as a basis for explaining the actions of exogenous opiates (see below). 4.2. EFFECTSOF OPIATES ON CENTRALGABA-ERGIC SYSTEMS In general, single effective doses of morphine do not produce significant changes in the whole brain GABA contents of mice or rats (Roberts et al., 1958; Clouet and Neidle, 1970). However, the GABA contents and glutamate-c~-decarboxylase (GAD) activities of some brain regions of rats were altered after acute or chronic morphine treatment (Linet al., 1973; Kuschinsky et al., 1976; Takanada et al., 1976). Morphine (20 or 30 mg/kg, i.p.) caused modest increases in the GABA contents and GAD activities of certain regions of the rat spinal cord and marked increases in certain regions of the thalamus (Kuriyama and Yoneda, 1976; Yoneda et al., 1977). The GABA contents of the ventrolateral part of the ventral nucleus (VM) and the entopeduncular nucleus (EP) were increased in morphine-treated animals; these changes were prevented by pretreatment with levallorphan and were not produced by analgesic doses of Na +salicylate or pentazocine (Yoneda et al., 1977). Since the VM is involved in pain perception, and since no increases in thalamic GABA content were detected in morphinetolerant and -dependent rats, the effects produced by morphine might have been specifically related to its analgesic action. Acutely-administered morphine in rats also produced increases in GABA content and GAD activity in the dorsal parts of the dorsal horn and surroundings of the central canal of the spinal cord, areas which contain inhibitory GABA-ergic interneurones (Kuriyama and Yoneda, 1978). Regarding GABA turnover, acutely-administered morphine decreased the incorporation of labelled carbon atoms from glucose into GABA in rat brain (Bachelard and Lindsay, 1966), and systemically administered morphine decreased striatal GABA turnover (Moroni et al., 1978). Physically-dependent rats that were permitted to self-administer morphine showed increases in striatal GABA turnover as compared with their yoked morphine-infused or yoked vehicle-infused controls (Smith et al., 1980). van der Heyden and colleagues (1980) showed that the in vivo release of GABA from the striatum of anaesthetized rats was inhibited by perfusion with morphine, and that this action was blocked by nalorphine (10 #M). Also, GABA and muscimol inhibited K+-evoked release of MET-enkephalin from rat striatal slices in vitro by an effect that was reversed by picrotoxin (Osborne and Herz, 1980). Thus, GABA might modulate striatal enkephalin release. Ligand-binding studies have shown that opiates (e.g., naloxone, morphine, levorphanol) can inhibit Na+-independent [3H]GABA binding to human cerebellar homogenates with low potencies (EC50 -~ 250-400/~M; Dingledine et al., 1978). Acutely-administered morphine-SO4 (25 mg/kg, i.p.) to rats also decreased [3H]GABA binding to particles prepared from cerebellum, cerebral cortex and striatum, this effect being due to a selective decrease in the number of high-affinity GABA binding sites (Ticku and Huffman, 1980). However, in rats that were physically dependent on morphine, the decreases in GABA binding that occurred in cerebellum and striatum were due to a decrease in the number of low-affinity GABA binding sites. Therefore, high- and low-affinity GABA

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binding sites might play a differential role during various morphine treatments. Some opiate agonists were more potent in displacing [3H]strychnine than [3H]GABA binding to a membrane preparation of rat brain stem-spinal cord, but naloxone was more potent as a displacer of [3H]GABA than of [3H]strychnine (Goldinger et al., 1981).

4.3. EFFECTSOF GABA-ERGIC AGENTS ON ANALGESIAPRODUCEDBY OPIATES OR OPIOID PEPTIDES Muscimol potentiated the analgesic effects of systemically-administered morphine in the mouse hot-plate test and in the rat tail-flick test (Biggio et al., 1977). Bicuculline antagonized morphine action in the mouse tail-compression test (Yoneda et al., 1976). However, in other studies, muscimol produced only a very slight increase in morphine analgesia in the hot-plate test and did not alter morphine analgesia in the wire-grid test (Christensen et al., 1978). Intracerebroventricular (i.c.v.) injections of muscimol antagonized the antinociceptive effect of subcutaneously- or i.c.v.-administered morphine in rats (Mantegazza et al. 1979), and i.c.v.-administered GABA antagonized the analgesic effects of morphine in mice and of D-ALA2-MET-enkephalinamide in rats (Izumi et al., 1980; Yamamoto et al., 1981). Pretreatments with muscimol (i.c.v.) antagonized both morphineand fl-endorphin-induced analgesia, and i.c.v.-injected isoguvacine (a potent GABA-agonist that does not readily penetrate the blood-brain barrier), nipecotic acid, and guvacine (inhibitors of GABA transport) antagonized the analgesic effect of morphine in rats (Mantegazza et al., 1980). Thus, i.c.v, injections of GABA-ergic agents produce effects that are opposite to those of systemic injections. Administration of aminooxyacetic acid (AOAA; a non-selective inhibitor of GABA-T) decreased the analgesic action of morphine in the mouse tail-flick test (Ho et al., 1976), but AOAA increased the action of methadone in the rat foot-shock test (Kii~iriiiinen and Vikberg, 1976) and prolonged the effect of a high dose of morphine in the mouse tailcompression test (Yoneda et al., 1976). Administration of the irreversible GABA-T inhibitors y-acetylenic-GABA and 7-vinyl-GABA increased morphine analgesia (hot-plate test) by an action that was more pronounced in tolerant mice than in naive mice (Contreras et al., 1979). The analgesic action of these irreversible GABA-T inhibitors was antagonized by bicuculline in rats (tail-stimulation test), but was not prevented by naloxone in mice (hot-plate test) (Buckett, 1980). Only the (+)-stereoisomer of ~,-vinyl-GABA (the isomer that is active as a GABA-T inhibitor) had antinociceptive activity. Preliminary experiments have also indicated that intraperitoneal treatment of rats with 7-vinyl-GABA for three days can reduce voluntary oral intake of morphine in morphine-dependent rats (Buckett, 1981). In general, these studies have indicated that increases in cerebral GABA content are correlated with an enhancement of opiate action.

4.4. ANALGESIA INDUCED BY GABA-AGONISTS, G A B A - T INHIBITORS, OR G A B A UPTAKE BLOCKERS

Muscimol and THIP were active orally and parenterally in producing analgesic actions (Hill et al., 1981). THIP and baclofen (see Section 8) were ~ 3 times less potent than morphine and 5-15 times less potent than muscimol in the various tests employed. The analgesic actions of THIP, muscimol or baclofen (mouse hot-plate test) were not reversed by 5-minute pretreatments with naloxone or bicuculline, indicating that these substances do not intereact directly with morphine-receptors or with classic bicucullinesensitive GABA-receptors (Hill et al., 1981). THIP a~nd muscimol might produce analgesia by activating baclofen-sensitive, bicuculline-insensitive GABA-receptors (see Bowery et al., 1980). Another recent study has indicated that reaction times were increased in the mouse hot-plate and tail-immersion tests by THIP and by kojic amine (another directacting GABA-agonist), as well as by 7-vinyl-GABA and by the GABA uptake inhibitor nipecotic acid ethyl ester (Kendall et al., 1981). These actions were also not reversed by

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naloxone, but, since they were reversed by atropine it was suggested that they might be secondary to a GABA-mediated increase in cerebral cholinergic function. It is also of interest that intraperitoneally-injected di-n-propylacetate can produce a behavioral syndrome resembling morphine abstinence behavior in rats and that this behavior can be prevented by treatment with picrotoxin or bicuculline (de Boer et al., 1977, 1980; Van der Laan and Bruinvels, 1981). 4.5. COMMENT ON GABA-ERGIC ANALGESIA

The recent study of Grau and co-workers (1981) on long-term stress-induced analgesia might offer some clues for further study of naloxone-insensitive GABA-related analgesia. In their experiments, exposure of rats to a series of inescapable shocks produced both an early naltrexone-insensitive and a late naltrexone-reversible analgesic reaction. The early naltrexone-insensitive reaction could be related to GABA-ergic systems. Analgesia induced by ~-adrenergic agonists is also not sensitive to naloxone (see Fielding and Lal, 1981). Thus, one might consider that GABA-related analgesia might somehow involve central noradrenergic mechanisms. The finding that the analgesic actions of THIP and muscimol were bicuculline-insensitive (Hill et al., 1981) might simply mean that even though GABA itself activates both bicuculline-sensitive and bicuculline-insensitive receptors, it is only the bicuculline-insensitive GABA-receptors that are involved in GABA's analgesic action; i.e., the analgesic action of GABA might be due to an activation of those GABA-receptors that can also be activated by baclofen.

5. Endogenous Opioids and Analgesia In a recent review article, Olson et al. (1981) expressed little doubt that most opioid peptides and their antagonists can influence pain sensitivity, although the underlying mechanisms are not yet clear; the reader is referred to this review for thorough coverage of the relevant data. Only a few pertinent studies will be mentioned here. Antinociceptive effects have been produced in various mammals after central administration of several endorphinomimetics (e.g., MET-enkephalin, fl-endorphin, D-ALA2MET-enkephalin; see, e.g., Inturrisi et al., 1980; Larson et al., 1980; Oyama et al., 1980; Rosenfeld and Stocco, 1980; Tseng et al., 1980), whereas systemic administration of endorphinomimetics is generally ineffective (e.g., Inturrisi et al., 1980). Also, bacitracin, an agent which inhibits CNS peptidases that catabolize endorphins and enkephalins, produces analgesia in mice (Simmons and Ritzmann, 1980). At the human level, analgesia has been produced by intrathecally-administered fl-endorphin (Oyama et al., 1980), and acupuncture-induced analgesia might be mediated by endogenous opiates (Lee et al., 1980; Fu et al., 1980). In general, analgesia produced by endogenous opioids does not differ markedly form that produced by exogenous opiates (e.g. morphine); i.e., tolerance and dependence are produced by endogenous opioids, and cross-tolerance between morphine and endogenous opioids has been shown (e.g., Zieglg~nsberger et al., 1976; Bhargava, 1980; Huidoboro-Toro and Way, 1980; Tortella and Moreton, 1980). However, some dissociation between morphine-analgesia and endorphinomimetic action was indicated in a recent study which showed that slowing of the degradation of MET- and LEU-enkephalin by D-phenylalanine decreased the analgesia produced by cold-water swim stress, but not that produced by morphine (Bodnar et al., 1980). Other studies have indicated that swim stress-induced analgesia might be only partly decreased by naloxone, i.e. only partly dependent on endogenous opioids (see Chesher et al., 1980). More recently, acute warmwater swim stress was shown to increase the density of forebrain GABA binding sites in mice (Johnston et al., 1982). Although it is not yet clear, certain physiological stresses might produce analgesia that is related to GABA.

[:'. V. DEFIiUDIS

6. Relationship Between GABA and Endogenous Opioids in Analgesia; Some Effects of Benzodiazepines

As mentioned above, GABA inhibited the analgesia produced by D-ALA2-MET-enkephalinamide in rats (Izumi et al., 1980), and muscimol antagonized/~-endorphin-induced analgesia in rats (Mantegazza et al., 1980). Other biochemical (Moroni et al., 1978; Osborne and Herz, 1980) and behavioral (Lorens and Sainati, 1978; Stapleton et al., 1979) studies have indicated that both GABA and benzodiazepines interact with endogenous opioid systems. The sedativehypnotic, anticonvulsant, anxiolytic, muscle-relaxant and appetite-enhancing effects of benzodiazepines might occur via their facilitation of central GABA-ergic mechanisms (e.g., Costa et al. 1975; Billingsley and Kubena, 1978; Guidotti, 1978; Haefely, 1979; Fletcher et al., 1980; Costa et al., 1981). Benzodiazepines might also influence analgesic mechanisms by facilitating central GABA-ergic mechanisms. In this regard, Squires (1981) has suggested that all benzodiazepine-receptors might be coupled indirectly to GABA-receptors through anion binding sites. However, it should be understood that benzodiazepines might also influence the contents and/or turnover rates of other neurotransmitters, such as ACh (Consolo et al., 1975), catecholamines (e.g., Corrodi et al., 1967) and 5-HT (e.g. Stein et al., 1975), which appear to be involved in analgesic mechanisms. Benzodiazepines might modulate striatal enkephalinergic mechanisms by interacting with GABA-ergic systems. Thus, acute treatment of rats with diazepam caused a decrease in enkephalin content of the striatum and an increase in the enkephalin content of the hypothalamus (Duka et al., 1979, 1980). As the decrease in striatal enkephalin produced by diazepam was mimicked by muscimol and by AOAA and reversed by bicuculline, it was considered to be GABA-ergic; this effect was also antagonized by naloxone. Longterm treatment of rats (28 days) with benzodiazepines caused an increase in striatal MET-enkephalin content (Wiister et al., 1980). Taken together, these studies support the idea that endogenous opioid peptides are involved in GABA-benzodiazepine interactions (see also Billingsley and Kubena, 1978; Lorens and Sainati, 1978; Jordan et al., 1979). Excitation of hippocampal pyramidal neurones produced by opiates or opioid peptides can be antagonized by iontophoretically-applied naloxone or bicuculline (Zieglg~insberger et al., 1979). Thus, opioids might excite pyramidal neurones indirectly by inhibiting neighboring inhibitory (probably GABA-ergic) interneurones (see also Siggins and Zieglg~insberger, 1981). As enkephalin markedly attenuates a variety of GABA-ergic inhibitory pathways in the CNS while not affecting the action of GABA itself, it has been suggested that inhibitory interneurones might be primary targets for opioid peptidecontaining pathways and that disinhibition might be involved in opioid peptide action in the CNS (Nicoll et al., 1980). Blockade of GABA release from nerve terminals was considered to be a possible explanation for enkephalin-induced disinhibition.

7. Benzodiazepines and Cardiovascular Function

In addition to their other actions (see Section 6) benzodiazepines appear to affect cardiovascular function. Haefely (1979) has reported that therapeutic doses of benzodiazepines potently reduce autonomic (cardiovascular) reponses to direct electrical stimulation of the hypothalamus and other brain structures, and that the "damping" effect of benzodiazepines on the central substrates of sympathetic, parasympathetic and hormonal activities is the basis of their therapeutic use in psychosomatic, cardiovascular, and other disorders. It is also noteworthy that benzodiazepines are heavily prescribed for cardiovascular disease, such as hypertension (Blackwell, 1975), and that benzodiazepines can produce decreases in central sympathetic outflow and blood pressure in experimental animals (e.g., Chai and Wang, 1966; Sigg et al., 1971; Antonaccio and Halley, 1975; Bolme and Fuxe, 1977; Antonaccio et al., 1978a, b). Regarding the involvement of a GABA-ergic system in the cardiovascular actions of benzodiazepines, bicuculline pre-

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vented the inhibitory effects of diazepam on pressor responses to diencephalic stimulation (Antonaccio et al., 1978a). From a recent study, Whitehead and co-workers (1977) concluded that psychological complaints in hypertensive patients reliably led to the prescription of benzodiazepines, and that these drugs reduced both psychological complaints and blood pressure in a significant number of cases. Intravenous administration of diazepam to humans typically produces a modest decrease in systolic blood pressure, a transient decrease in left ventricular end-diastolic pressure, and a decrease in left ventricular stroke work (Dalen et al., 1969; Rao et al., 1973; Markiewicz et al., 1976; Cot6 et al., 1976). Also, acute vasodilatation, leading to profound hypotension, has occurred in humans following induction of anaesthesia with intravenous diazepam plus nitrous oxide (Falk et al., 1978). These studies support the belief benzodiazepines are useful for reducing blood pressure in man. At the biochemical level, benzodiazepine binding sites have been demonstrated on rat mast cells (Taniguchi et al., 1980), in platelets (Wang et al., 1980) and in kidney and heart (Taniguchi et al., 1981; Davies and Huston, 1981). The number of platelet benzodiazepine binding sites (Bm,x) was higher in SHR than in WKY rats at 4 and 20 weeks of age, and the Bma × of kidney benzodiazepine binding sites of SHR was lower than that of WKY at both ages; binding constants (KD vaues) for diazepam binding did not differ between SHR and WKY (Taniguchi et al., 1981). As such changes in the Bin,, of benzodiazepine binding sites were not related to hypertension per se (since SHRs are not hypertensive at 4 weeks of age), these might represent biochemical markers of essential hypertension. In contrast to results obtained with SHR, the Bm,x of renal benzodiazepine binding sites was higher in desoxycorticosterone/salt uninephrectomized hypertensive rats than in control rats (Regan et al., 1980). [3H]Diazepam binding sites have also been detected in guineapig heart, and such binding sites (like those found in kidney and mast cells; see above) differed from those of brain (Davies and Huston, 1981). Since it has been proposed that diazepam has a coronary vasodilator action in experimental animals and in man (Ikram et al., 1973; Daniell, 1975), it is of interest that dipyridamole (a coronary vasodilator in clinical use) has been shown to interact with these [3H]diazepam binding sites of guineapig heart (Davies and Huston, 1981).

8. Baclofen--A Derivative of GABA With Analgesic and Cardiovascular Actions

Baclofen (fl-(4-chlorophenyl)-7-aminobutyric acid; Lioresal®), is clinically effective for treating spasticity (Birkmayer, 1972; Pinto et al., 1972; Pedersen et al., 1974). Although structurally similar to GABA, baciofen does not appear to mimic GABA's action, or to interact with bicuculline-sensitive GABA-receptors in the CNS (Curtis et al., 1974; Davidoff and Sears, 1974; Davies and Watkins, 1974; but see Fox et al., 1978; Lalley, 1980a). Baclofen might act at bicuculline-insensitive GABA-receptors that have been recently shown to exist in the CNS (Bowery et al., 1980, 1981). Monoaminergic mechanisms might also be involved in baclofen action (Da Prada and Keller, 1976; Gianutsos and Moore, 1977; And6n and Wachtel, 1978; Waldmeier and Fehr, 1978; Waldmeier and Maitre, 1978). Pinto and co-workers (1972) found that baclofen could suppress pain in patients suffering from spastic conditions. In an attempt to clarify this analgesic action, Levy and Proudfit (1977) found that baclofen produced dose-dependent antinocisponsive activity in the stretch, hot-plate and tail-flick tests in mice. Since the analgesic effect of baclofen was not reversed by naloxone, and since cross-tolerance between morphine- and baclofeninduced analgesia could not be demonstrated, they concluded that the mechanism of action of baclofen differs from that of morphine. However, as neither baclofen- nor morphine-induced analgesia in rats was altered by transecting the brain stem between the superior and inferior colliculi, but as the actions of both drugs were greatly reduced following section of the medulla at a point 3 mm rostral to the obex, the rostral margin of neuronal substrates involved in the actions of both drugs lies somewhere in the pons

10

[:. \ . DI Fl:t DIS

or anterior third of the medulla; thus, analgesia induced by baclofen and by morphine might involve, at least in part, common neuronal substrates (Proudfit and Levy, 1978). Intracerebral administration of baclofen also produced analgesia in rats (Levy and Proudfit, 1979). Although baclofen enhances the release of MET-enkephalin from brain slices (Sawynok and LaBella, 1981a), endogenous opioid release might not mediate its analgesic action since this analgesia, like that produced by TH1P or muscimol (see Section 4.4.), is not blocked by naloxone (Levy and Proudfit, 1977; Sawynok and LaBella, 1981b; Hill et al., 1981). However, baclofen overdose does produce symptoms that resemble those produced by opiate overdose (Jaffe and Martin, 1975; see Sawynok and LaBella, 1981b), indicating that endogenous opiates could be released by high doses of baclofen. Baclofen administration can also affect cardiovascular mechanisms. This agent can lower blood pressure in man (Pinto et al., 1972) and in anaesthetized experimental animals (Persson and Henning, 1980). Intravenously-administered baclofen produced a transient decrease in arterial blood pressure in urethane- or urethane-plus-pentobarbitoneanaesthetized rats in lower doses (<5 x 10 Smol) and a marked and prolonged pressor response and an increase in heart rate in higher doses (> 5 x 10 7 mol) (Chahl and Walker, 1980). The pressor response to baclofen did not appear to be due to an activation of central GABA-receptors since it was enhanced by bicuculline. Chahl and Walker (1980) suggested that higher doses of baclofen might affect cardiovascular function by acting on central sympathetic mechanisms. In conscious rats, intraperitoneal (5 mg/kg) or i.c.v, injections of baclofen produced a sustained hypertension and tachycardia (Persson and Henning, 1979). As this action of baclofen was blocked by phenoxybenzamine pretreatment and attenuated following catecholamine depletion, an intact noradrenergic system appears to be important for these actions of baclofen. Further studies revealed that the hypertension and tachycardia produced by baclofen (5 mg/kg, i.p.) in conscious rats was prevented by a mid-collicular decerebration, but not by brain transection rostral to the hypothalamus, and that direct application of baclofen (50 ng) to the region of the nucleus tractus solitarii produced a pressor response, whereas applications to regions of the hypothalamus were without effect (Persson, 1981). It was concluded that systemically-administered baclofen might act in the nucleus tractus solitarii to produce hypertension. Baclofen, administered intravenously to cats, increased blood pressure when buffer nerves were intact, and converted depressor responses that were produced by electrical stimulation of the carotid sinus nerve, aortic nerve or cervical vagus nerve to pressor responses (Lalley, 1980a). The original depressor responses could be restored by bicuculline or picrotoxin. Lalley (1980a) concluded that baclofen has direct inhibitory and remote disinhibitory effects, but that an explanation of the vasomotor effects of baclofen as a GABA-mimetic is not yet certain (see also Lalley, 1980b).

9. Concluding Remarks From the foregoing discussion it seems clear that central GABA-ergic and endogenous opioid systems are involved in both cardiovascular function and analgesia. However, the interrelationship of endogenous opioids and GABA in analgesia is not yet clear. Thus, GABA-related analgesia is either not mediated by endogenous opioids, or involves a naloxone-insensitive endogenous opioid system. Regarding the latter possibility, it has been shown that inhibition of the spontaneous contractions of rat ileum by both LEUand MET-enkephalin was not affected by naloxone (Nakatsu et al., 1981). The lack of cross-tolerance between morphine and LEU-enkephalin in mouse vas deferens (Illes et al., 1980) also indicates that certain opiate receptors might be atypical. Like GABArelated analgesia, the analgesia produced by e-adrenergic agonists as well as certain other types of analgesia (e.g., some kinds of shock-induced analgesia, or analgesia produced by centrifugal rotation in rats), differ from the analgesia produced by exogenous opiates or by known endogenous opioids (in most cases) since these are naloxone-insensitive (e.g.

ANALGESIAand CARDIOVASCULARFUNCTION

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Hayes et al., 1978a, b; Reddy et al., 1980; Lewis et al., 1980, 1981). It remains to be shown whether or not these types of naloxone-insensitive analgesia involve GABA-ergic systems. It seems likely that other endogenous analgesic substances will be discovered in the future (see e.g., Cox et al., 1980); such substances might mediate the above-mentioned types of analgesia and their actions might not be sensitive to naloxone. The relationship between analgesia and cardiovascular function seems clear, especially from the results which have revealed that pain thresholds are increased in both the SHR and in humans with hypertension; this supports a role for endogenous opioids in cardiovascular function. Studies with benzodiazepines (the effects of which appear to be mediated mainly by a facilitatory action on GABA-ergic systems) and with baclofen (an agent which has both analgesic and cardiovascular actions, and which appears to act at bicuculline-insensitive GABA-receptors in the CNS) have further strengthened the link between analgesia and cardiovascular function, as well as the interrelationship of GABA and endogenous opioids. The findings that food restriction and weight loss reduce blood pressure in the SHR (Wright et al., 1981), and that administration of certain GABAagonists, such as THIP, can produce anorexigenic effects (Blavet et al., 1982a, b),analgesic effects (Hill et al. 1981), and reductions in blood pressure (e.g., Snyder et al., 1980), indicate that the further development of GABA-agonists as therapeutic agents will be fruitful. References ANDf~N, N.-E. and WACHTEL, H. (1978) Some effects of GABA and GABA-Iike drugs on central catecholamine mechanisms. 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