The effect of Suvorexant on morphine-induced tolerance and dependence: role of NMDA, AMPA, CREB, p-CREB, ERK, p-ERK

Introduction: Drug use is an abnormal behavior that results in specific clinical or psychological injuries. One of the problems with drug use such as morphine in the clinical setting is the tolerance to its effects which prevents its long-term use. Nowadays, with the identification of the effects of orexin and its receptors on rewarding behaviors and drug addiction, orexin receptors have been considered as a pilot target for the development of drugs with high therapeutic potential to treat wide range of drug addictions. Suvorexant is an antagonist of both types of orexin receptors. The aim of the present study was to evaluate the therapeutic effect of Suvorexant on morphine-induced tolerance and dependence in mice.Methods: For morphine tolerance and dependence, morphine was injected 3 times daily for 3 days (50, 50 and 75 mg/kg). To evaluate the effect of Suvorexant on morphine tolerance and dependence, before morphine injection, Suvorexant (30, 60 and 90 mg/kg) was injected intraperitoneally to mice. At the end, behavioral tests were performed and the mice brains were used for Western blot analysis.Result: Suvorexant at all doses significantly reduced morphine-induced tolerance and dependence.Suvorexant also increased p-CREB / CREB protein ratio and decreased p-ERK / ERK protein ratio compared to morphine.Conclusion: Morphine promotes adaptation and tolerance through different pathways. It has been shown that morphine can induce tolerance and dependence by altering the release of glutamate and dopamine and intracellular pathways such as NMDA, AMPA, p-ERK/ERK and p-CREB/CREB. The results of this study showed that Suvorexant could be effective in reducing morphine tolerance and dependence. The efficacy of Suvorexant is probably through alterations in the expression of CREB and p-ERK proteins.