Evaluation of the effect of Dextromethorphan and Ketoconazole on morphine induced tolerance in mice

Abstract

Introduction: The long term use of opioid analgesics is limited due to the development of tolerance and their adverse effects. One of the reasons for the tolerance incidence to morphine is the overactivity of NMDA receptors. Dextromethorphan inhibits these receptors. Also, increased expression of P-glycoprotein gene in blood-brain barrier causes tolerance. Ketoconazole inhibits P-glycoproteins. Aim: The aim of the present study was to evaluate the effects of chronic intraperitoneal administration of dextromethorphan and ketoconazole on the incidence of morphine analgesic tolerance in male mice. Method: 81 male mice in a weight range of 25 to 35 grams were randomly divided into 9 equal groups and underwent dextromethorphan and ketoconazole for 2 weeks. Different doses of dextromethorphan (25 , 50 , 75 mg/kg) and ketoconazole (25 , 50 , 100 mg/kg) were injected. The drugs injected every day half an hour before the daily injection of morphine. On the 15th day analgesic effects of morphine test dose (9 mg / kg, ip) evaluated by hot plate method. After behavioral studies in different groups, the animals were anesthetized by injection of ketamine with xylazine. Finally blood samples were collected for MDA and TAC estimation. Result: The results showed a significant effect (p <0.01) of 50,100 mg / kg doses of ketoconazole and 50,75 mg / kg doses of dextromethorphan in reducing tolerance due to morphine injection for 14-day. Conclusion: Co-injection of the minimum doses of dextromethorphan and ketoconazole had a statistically better effect than injection of each of them alone.