The potential role of the orexin reward system in future treatments for opioid drug abuse

Abstract

Despite a history of more than a century of intense research in drug addiction, with currently available medication and behavioral therapy, the rate of relapse to drug use is 40–60 percent within a year after the cessation of treatment. The discovery of the neuropeptide orexin/hypocretin in 1998 and subsequent research during the past 20 years revealed an important role for the lateral hypothalamus (LH) in driving the reward pathway. The present review includes an overview of the orexinergic system and focuses on the role of LH orexin neurons targeting different components of the brain’s reward pathway in addictive behaviors. Among major animal models of drug reinforcement and addictive behaviors, we narrowed our focus to include conditioned place preference (CPP) and self-administration methods. In this regard, studies on both orexin-1 receptors (OX1Rs) and orexin-2 receptors (OX2Rs) have shown some positive results, suggesting that single orexin receptor antagonists (SORAs) and dual orexin receptor antagonists (DORAs) may hold promising efficacy in the treatment of addiction compared to the currently used methods. We conclude that since current evidence is still preliminary, development of new SORA and DORA compounds and their evaluation in animal and clinical studies will guide us in our future efforts for developing effective medication.