Possible mechanisms of action in melatonin reversal of morphine tolerance and dependence in mice

In our earlier study, we reported the ability of melatonin to reverse the d evelopment of morphine tolerance and dependence in mice. In the present stu dy, we attempted to analyse the possible involvement of putative melatonin receptors, central and peripheral benzodiazepine receptors and the nitric o xide (NO) system in the mechanism of melatonin reversal of morphine toleran ce and dependence in mice. Co-administration of L-N-G-nitro arginine methyl ester (L-NAME) or melatonin with morphine during the induction phase (days 1-9) delayed the development of tolerance to the anti-nociceptive action o f morphine and also reversed naloxone precipitated withdrawal jumpings. L-a rginine administration during the induction phase enhanced the development of tolerance to the anti-nociceptive effect of morphine but had no effect o n the naloxone-precipitated withdrawal response. During the expression phas e (day 10), acute administration of melatonin or L-NAME reversed, whereas L -arginine facilitated, naloxone-precipitated withdrawal jumping in morphine -tolerant mice, but none of these drags affected the nociceptive threshold in morphine-tolerant mice. Further, co-administration of melatonin or L-NAM E with L-arginine during the induction phase antagonized later the effects on the development of morphine tolerance. Also, prior administration of mel atonin or L-NAME reversed the L-arginine potentiation of naloxone-precipita ted withdrawal jumping in morphine tolerant mice. Among the antagonists for putative melatonin receptors studied, neither luzindole (melatonin MT1 and MT2 receptor antagonist) nor prazosin (melatonin MT, receptor antagonist) antagonized the melatonin reversal of morphine tolerance and dependence. 1- (2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide (PK 11195), a peripheral but not central benzodiazepine receptor antagonist, fl umazenil, partially antagonized the melatonin reversal of naloxone-precipit ated withdrawal jumping in morphine-dependent mice, but had no effect on th e reversal of morphine tolerance induced by melatonin. Overall, the present observations suggest that the melatonin-induced reversal of morphine toler ance and dependence may involve its ability to suppress nitric oxide syntha se (NOS) activity. Further, the melatonin-induced reversal of morphine tole rance and dependence is not mediated through its actions via putative melat onin receptors. The agonistic activity of melatonin towards peripheral benz odiazepine receptors may partially contribute to the suppression of morphin e dependence but not to the reversal of tolerance to the analgesic activity of morphine. (C) 2000 Elsevier Science B.V. All rights reserved.