In our earlier study, we reported the ability of melatonin to reverse the development
of morphine tolerance and dependence in mice. In the present study, we attempted to
analyse the possible involvement of putative melatonin receptors, central and peripheral
benzodiazepine receptors and the nitric oxide (NO) system in the mechanism of melatonin
reversal of morphine tolerance 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 of
morphine and also reversed naloxone precipitated withdrawal jumpings. L-arginine administration
during the induction phase enhanced the development of tolerance to the anti-nociceptive
effect of morphine but had no effect on the naloxone-precipitated withdrawal response.
During the expression phase (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 drugs affected the nociceptive threshold
in morphine-tolerant mice. Further, co-administration of melatonin or L-NAME with
L-arginine during the induction phase antagonized later the effects on the development
of morphine tolerance. Also, prior administration of melatonin or L-NAME reversed
the L-arginine potentiation of naloxone-precipitated 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 MT3
receptor antagonist) antagonized the melatonin reversal of morphine tolerance and
dependence. 1-(2-Chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxam
ide (PK11195), a peripheral but not central benzodiazepine receptor antagonist, flumazenil,
partially antagonized the melatonin reversal of naloxone-precipitated withdrawal jumping
in morphine-dependent mice, but had no effect on the reversal of morphine tolerance
induced by melatonin. Overall, the present observations suggest that the melatonin-induced
reversal of morphine tolerance and dependence may involve its ability to suppress
nitric oxide synthase (NOS) activity. Further, the melatonin-induced reversal of morphine
tolerance and dependence is not mediated through its actions via putative melatonin
receptors. The agonistic activity of melatonin towards peripheral benzodiazepine receptors
may partially contribute to the suppression of morphine dependence but not to the
reversal of tolerance to the analgesic activity of morphine.