Evaluation of the effects of azithromycin and loperamide on morphine-induced tolerance in mice

Abstract

Introduction: Morphine is one of the most widely used opioid analgesic that is used to control severe pain. Tolerance to the analgesic effects of morphine is one of the problems caused by the chronic use of morphine. Several mechanisms (inhibition of NMDA receptors, increased p-gp gene expression, etc.) are involved in the emergence of tolerance to the analgesic effects of morphine; Loperamide is one of the compounds related to opioids, this drug is a p-gp substrate, on the other hand, azithromycin is one of the macrolide antibiotics and is also a p-gp inhibitor. Purpose: The purpose of this study was to investigate the effects of loperamide and azithromycin in reducing tolerance to the analgesic effects of morphine in mice. Methods: 90 male mice in 9 groups of 10 in the weight range of 20-30 grams were randomly selected and given drug regimens of Saline (10 ml/kg, ip) or Morphine (25 mg/kg ip) to create Tolerance to morphine was received once a day for fourteen days. Then on the fifteenth day, different doses of azithromycin (50-100-200 mg/kg, ip) and loperamide (0.1-0.2-0.4 mg/kg, ip) and loperamide (0.1mg/kg, ip) + azithromycin (50mg/ kg, ip) half an hour before the test injection, morphine (9 mg/kg, ip) was injected into the mice. Finally, the analgesic effects caused by the morphine dose test (9 mg/kg, ip)that were evaluated in the studied groups by the Hot plate method for one hour.Results: The results showed that different doses of loperamide (0.1-0.2-0.4mg/kg, ip) do not have a significant effect on reversing tolerance to the analgesic effects caused by morphine. while in the injection of different doses of azithromycin (50-100-200 mg/kg, ip) a significant effect of Azithromycin (100mg/kg, ip) was effective in reversing the tolerance to the analgesic effects of morphine. In the combined injection of two drugs, loperamide (1mg/kg, ip) + azithromycin (50 mg/kg, ip), no significant effect was observed in reversing tolerance to analgesic effects. Conclusion: Azithromycin has beneficial effects in amounts (100mg/kg, ip) in reversing tolerance to the analgesic effects of morphine. Additional studies on the beneficial effects of azithromycin in humans are suggested.