¹Department of Pharmacology, Faculty of Pharmacy, Karadeniz Technical University, Trabzon, Türkiye
²Department of Medical Pharmacology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Türkiye Morphine tolerance is a serious clinical problem characterized by a decreased analgesic effect resulted from the long-term use of morphine with uncertain etiology and therapeutic interventions are limited. In this study, we aimed to investigate the effect of telmisartan in a mouse model of morphine-induced analgesic tolerance and the underlying mechanisms of its action. Morphine (10 mg/kg) was injected subcutaneously twice daily for five days. Mice were pretreated with Telmisartan (TEL; 5 and 15 mg/kg) orally by gavage 30 min before each morphine injection. L-NAME (10 mg/kg), L-arginine (L-ARG,300 mg/kg) or N-acetylcysteine (NAC, 50 mg/kg) was administered intraperitoneally 45 min prior to morphine. Analgesic efficacy was evaluated by hot-plate test on 1st, 3rd and 5th days, 60 min after morphine injection. Spinal cord samples of mice were used to examine the protein expressions of nNOS and iNOS by western blotting and total GSH content. Repeated morphine administration caused a significant decrease in analgesic efficacy, demonstrating the development of morphine tolerance. High-dose TEL treatment effectively prevented morphine-induced analgesic tolerance. L-ARG abolished the inhibitory effect of TEL on morphine tolerance, while LNAME and NAC did not alter. GSH level and nNOS expression were decreased, as well as iNOS expression was increased in the spinal cords from morphine-tolerant mice. TEL (15 mg/kg) treatment prevented the decrease in GSH level and the increase in iNOS expression of spinal cords. TEL would be a potential therapeutic candidate in preventing morphine tolerance through its activity on antioxidant systems and, in part, on the nitric oxide pathway. Keywords : hot-plate test; mice; morphine tolerance; nitric oxide; telmisartan