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The enkephalinase inhibitor thiorphan shows antinociceptive activity in mice
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PHARMACOLOGY
Irreversible inhibitors of GABA transaminase induce antinociceptive effects and potentiate morphine.--W.R. Buckett, Neuropharmacology, 19 (1980) 715--722 Several attempts have been made to ascribe a role for 7-aminobutyric acid (GABA) in antinociception although the results have been controversial. The awilability of the irreversible inhibitors of GABA-transaminase, 7-acetylenic GABA and 7-vinyl GABA which cause a marked rise in brain GABA concentrations permitted the determination of their a.ntinociceptive effects in relation to elevated cerebral GABA level. Following their i.p. administration an antinociceptive effect unaccompanied by ataxia was demonstrated in mice on the 52°C hot-plate and in rats in a tail-stimulation procedure and was maximal at 4--6 h after drug administration, which correlates temporally with reported maximal increases of brain GABA. The antinociceptive effect was antagonized by a subconvulsire dose of bicuculliDe (0.5 mg/kg, i.p.) in rats, but could not be prevented by naloxone (1 mg/kg, i.p.) in mice.Only the (+)-stereoisomer of 9"-vim,' GABA, active as a GABA-transaminase inhibitor, was antinociceptive. The effects appear to be causally related to elevated cerebral GABA levels. The profile of these agents in the tail stimulation test in rats suggests a specific antinociceptive effect since vocalization and vocalization afterdischarge were similarly affected. The analgesic actions of morphine in mice on the 56°C hot-plate were enhanced 5 h after the administration of 9'-acetylenic GABA or 7-vinyl GABA. The compounds did not alter the naloxone-precipitated morphine withdrawal syndrome in the rat. It is concluded that ~'-acetylenic GABA and T-vinyl GABA can produce distinct antinociceptive effects in rats and mice related to increased brain GABA levels, but which are n o t oploid-like in nature. The enkephalinase inhibitor thiorphan shows antinociceptive activity in m i c e . - B.P. Roques, M.C. Fournie-Zaluski, E. Soroca, J.M. Lecomte, B. Malfroy, C. Llorens and J.C. Schwartz, Nature (Lond.), 288 (1980) 286--288 There is both theoretical and therapeutic interest in establishing whether the signals conveyed by the enkephalins are turned off under the action of a specific peptidase which might, in this case, represent a target for a new class of psychoactive agents. Enkephalinase, a dipeptidyl carboxypeptidase cleaving the Gly3-Phe4 bond of enkephalins and distinct from angiotensin converting enzyme, might be selectively involved in enkephalinergic transmission. It is a membrane-bound enzyme whose localization in the vicinity of opiate receptors in the central nervous system is suggested by parallel regional and subcellular distributions as well as by the effects of lesions. Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogues, and its adaptive increase following chronic treatment with morphine. To investigate the functional role of this
415
enzyme further, a potent and specific enkephalinase inhibitor has been designed. In this paper the authors show that this compound, Thiorphan (DL3-mercapto-2-benzylpropanoyl)-glycine; patent no. 8008601) protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after either intracerebroventricular or systemic administration. In addition, Thiorphan itself displays antinociceptive activity which is blocked by naloxone, an antagonist of opiate receptors. Morphine enhances adenosine release from the in vivo rat cerebral cortex. -J.W. Phillis, Z.G. Jiang, B.J. Chelack and P.H. Wu, Europ. J. Pharmacol., 65 (1979) 97--100 Methylxanthines (caffeine, theophylline) have been reported to antagonize several different actions of morphine and it has been shown that morphine may depress acetylcholine release by releasing adenosine. In the present study the action of morphine on the release of adenosine from the intact cerebral cortex was investigated. Morphine (1 and 5 mg/kg), administered intravenously, increased the rate of efflux of purines from intact rat cerebral cortices prelabeled with [3H]adenosine. Naloxone antagonized morphine's action. It is suggested that the depressant actions of morphine on transmission in the central nervous system may be related to this enhancement of extracellular levels of adenosine and the adenine nucleotides.
MEDICINE " E m p t y neurone" theory as a research perspective of diseases of the nociceptive system. -- F. Sicuteri, J. Drug Res., November (special issue) (1980) 73-78 The main pathophysiological problem in migraine headache is whether the origin of pain is: (1) peripheral, according the conventional theory, in which case which structures are involved? muscles (tension), meningeal vessels, in relation to vasomotility or in relation to sensitization of end organs to one or many autacoids?, (2) central, a personal theory of the author. Central pain in migraine could be due to an altered turnover of neurotransmitters and neuropeptides. Further study is necessary in this field. As a matter of fact, many drugs (ergot alkaloids, methysergide, LSD-25, etc.) act as an analgetic only in migraine headache.
SURGERY Site of pain from the irritable b o w e l . - E.T. Swarbrick, J.E. Hegarty, L. Bat, C.B. Williams and A.M. Dawson, Lancet, 30 (1980) 443--446 This study demonstrated experimentally that colonic pain has in some extent localization to site of disorder.
PHARMACOLOGY
Irreversible inhibitors of GABA transaminase induce antinociceptive effects and potentiate morphine.--W.R. Buckett, Neuropharmacology, 19 (1980) 715--722 Several attempts have been made to ascribe a role for 7-aminobutyric acid (GABA) in antinociception although the results have been controversial. The awilability of the irreversible inhibitors of GABA-transaminase, 7-acetylenic GABA and 7-vinyl GABA which cause a marked rise in brain GABA concentrations permitted the determination of their a.ntinociceptive effects in relation to elevated cerebral GABA level. Following their i.p. administration an antinociceptive effect unaccompanied by ataxia was demonstrated in mice on the 52°C hot-plate and in rats in a tail-stimulation procedure and was maximal at 4--6 h after drug administration, which correlates temporally with reported maximal increases of brain GABA. The antinociceptive effect was antagonized by a subconvulsire dose of bicuculliDe (0.5 mg/kg, i.p.) in rats, but could not be prevented by naloxone (1 mg/kg, i.p.) in mice.Only the (+)-stereoisomer of 9"-vim,' GABA, active as a GABA-transaminase inhibitor, was antinociceptive. The effects appear to be causally related to elevated cerebral GABA levels. The profile of these agents in the tail stimulation test in rats suggests a specific antinociceptive effect since vocalization and vocalization afterdischarge were similarly affected. The analgesic actions of morphine in mice on the 56°C hot-plate were enhanced 5 h after the administration of 9'-acetylenic GABA or 7-vinyl GABA. The compounds did not alter the naloxone-precipitated morphine withdrawal syndrome in the rat. It is concluded that ~'-acetylenic GABA and T-vinyl GABA can produce distinct antinociceptive effects in rats and mice related to increased brain GABA levels, but which are n o t oploid-like in nature. The enkephalinase inhibitor thiorphan shows antinociceptive activity in m i c e . - B.P. Roques, M.C. Fournie-Zaluski, E. Soroca, J.M. Lecomte, B. Malfroy, C. Llorens and J.C. Schwartz, Nature (Lond.), 288 (1980) 286--288 There is both theoretical and therapeutic interest in establishing whether the signals conveyed by the enkephalins are turned off under the action of a specific peptidase which might, in this case, represent a target for a new class of psychoactive agents. Enkephalinase, a dipeptidyl carboxypeptidase cleaving the Gly3-Phe4 bond of enkephalins and distinct from angiotensin converting enzyme, might be selectively involved in enkephalinergic transmission. It is a membrane-bound enzyme whose localization in the vicinity of opiate receptors in the central nervous system is suggested by parallel regional and subcellular distributions as well as by the effects of lesions. Such a role is further supported by the ontogenetic development of enkephalinase, its substrate specificity accounting for the increased biological activity of several enkephalin analogues, and its adaptive increase following chronic treatment with morphine. To investigate the functional role of this
415
enzyme further, a potent and specific enkephalinase inhibitor has been designed. In this paper the authors show that this compound, Thiorphan (DL3-mercapto-2-benzylpropanoyl)-glycine; patent no. 8008601) protects the enkephalins from the action of enkephalinase in vitro in nanomolar concentration and in vivo after either intracerebroventricular or systemic administration. In addition, Thiorphan itself displays antinociceptive activity which is blocked by naloxone, an antagonist of opiate receptors. Morphine enhances adenosine release from the in vivo rat cerebral cortex. -J.W. Phillis, Z.G. Jiang, B.J. Chelack and P.H. Wu, Europ. J. Pharmacol., 65 (1979) 97--100 Methylxanthines (caffeine, theophylline) have been reported to antagonize several different actions of morphine and it has been shown that morphine may depress acetylcholine release by releasing adenosine. In the present study the action of morphine on the release of adenosine from the intact cerebral cortex was investigated. Morphine (1 and 5 mg/kg), administered intravenously, increased the rate of efflux of purines from intact rat cerebral cortices prelabeled with [3H]adenosine. Naloxone antagonized morphine's action. It is suggested that the depressant actions of morphine on transmission in the central nervous system may be related to this enhancement of extracellular levels of adenosine and the adenine nucleotides.
MEDICINE " E m p t y neurone" theory as a research perspective of diseases of the nociceptive system. -- F. Sicuteri, J. Drug Res., November (special issue) (1980) 73-78 The main pathophysiological problem in migraine headache is whether the origin of pain is: (1) peripheral, according the conventional theory, in which case which structures are involved? muscles (tension), meningeal vessels, in relation to vasomotility or in relation to sensitization of end organs to one or many autacoids?, (2) central, a personal theory of the author. Central pain in migraine could be due to an altered turnover of neurotransmitters and neuropeptides. Further study is necessary in this field. As a matter of fact, many drugs (ergot alkaloids, methysergide, LSD-25, etc.) act as an analgetic only in migraine headache.
SURGERY Site of pain from the irritable b o w e l . - E.T. Swarbrick, J.E. Hegarty, L. Bat, C.B. Williams and A.M. Dawson, Lancet, 30 (1980) 443--446 This study demonstrated experimentally that colonic pain has in some extent localization to site of disorder.