Evaluation of the effect of clarithromycin and ketoconazole on morphine induced tolerance in mice

Abstract

Introduction: Increased gene expression of P-glycoprotein in the blood-brain barrier is one of the reasons for tolerance to the analgesic effects of morphine. It is possible that the drug clarithromycin causes inhibition P-glycoprotein. Ketoconazole also has P-glycoprotein inhibition effects. In the present study, these two drugs were investigated in morphine-induced tolerance in mice.Aim: The aim of the present study was to evaluate the effects of different doses of intraperitoneal administration of clarithromycin and ketoconazole on the incidence of morphine analgesic tolerance in male mice.Methods: We selected 80 male mice as randomly in 8 groups of 10 in the weight range of 20-30 grams and received the following drug regimens. 1.Saline (10ml/kg, ip) for 14 days + saline (10ml/kg, ip) on the 15th day, 2- Morphine (30 mg/kg) for 14 days + saline (10ml/kg, ip) per day 15th, 3,4,5-morphine (30 mg/kg) for 14 days + clarithromycin (50, 100, 200 mg/kg) on the 15th day, 6,7,8-morphine (30 mg/kg) for 14 days+ Ketoconazole (0.1, 0.2, 0.4mg/kg) on the 15th day. In all the above groups, on the 15th day, one hour after the injection of saline or drugs, the morphine dose test was injected and half an hour later, the hot plate test was taken. The analgesic effects of morphine dose test (mg/kg, ip 9) were evaluated in the studied groups by hot plate method.Results: The results indicated a significant effect of reducing tolerance in doses (50, 100, 200 mg/kg, ip) of clarithromycin and doses (0.1, 0.2, 0.4 mg/kg, ip) of ketoconazole. Conclusion: According to the results of the present study, clarithromycin and ketoconazole in different doses reduce the occurrence of tolerance to the analgesic effects of morphine, and part of this effect may be related to the inhibitory effects of the P-glycoprotein pump of these drugs. It is also possible that the drug clarithromycin, with its anti-inflammatory effects, including inhibiting the migration of neutrophils and pro-inflammatory cytokines, increasing phagocytosis and the activity of natural killer cells, and inducing eosinophil apoptosis, was able to return the tolerance to the analgesic effects of morphine.