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 i nduce morphine tolerance and dependence. Go-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 tes ted 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 depende nce, it reduced the incidence of naloxone-induced withdrawal jumps without affecting the tolerance to analgesic effect. Co-administration of flumazeni l (2 mg/kg, i.p.), a central benzodiazepine (BZ) receptor antagonist had no effect on melatonin response, whereas peripheral antagonist for BZ recepto r 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 mela tonin reverses development of tolerance and dependence tb morphine, and thi s action possibly involved peripheral benzodiazepine receptors. (C) 1999 El sevier Science B.V. All rights reserved.