Reversal of morphine tolerance and dependence by melatonin: possible role of central and peripheral benzodiazepine receptors.

Possible reversal by melatonin of morphine-induced tolerance and dependence was studied in mice. A 10-day repeated injection regimen was followed to induce morphine tolerance and dependence. Co-administration of melatonin (1-10 mg/kg, i.p.) with morphine (10 mg/kg, s.c.) during the induction phase (day 1 to 9) reversed the development of opioid tolerance and dependence tested on 10th day. On the other hand acute administration of melatonin (1-10 mg/kg) on the 10th day, ie. during the expression phase of morphine dependence, it reduced the incidence of naloxone-induced withdrawal jumps without affecting the tolerance to analgesic effect. Co-administration of flumazenil (2 mg/kg, i.p.), a central benzodiazepine (BZ) receptor antagonist had no effect on melatonin response, whereas peripheral antagonist for BZ receptor PK11195 (2 mg/kg, i.p.) significantly reversed the attenuating effect of melatonin on physical dependence both during induction and expression phase of morphine tolerance and dependence. These observations suggest that melatonin reverses development of tolerance and dependence to morphine, and this action possibly involved peripheral benzodiazepine receptors. Copyright 1999 Elsevier Science B.V.