Peyman Esmaili-Shahzade-Ali-Akbari - ۱. Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran ۲. Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
Amir Ghaderi - Department of Addiction Studies, School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
Atena Sadeghi - Department of Microbiology, Faculty of Medicine, Shahed University, Tehran, Iran
Fatemeh Nejat - Department of Biology and Health Sciences, Meredith College, Raleigh, North Carolina, USA
Alireza Mehramiz - Department of Physical Therapy, Faculty of Paramedical and Rehabilitation Science, Mashhad University of Medical Sciences, Mashhad, Iran

The orexinergic system and its receptors are involved in many physiological processes. Their functions in energy homeostasis, arousal, cognition, stress processing, endocrine functions, and pain modulation have been investigated. Many studies have shownthat the orexinergic system cooperates with the dopaminergic system in the addiction process. Emerging evidence suggests that the orexinergic system can be effective in the induction of drug dependence and tolerance. Therefore, several researches have been conducted on the effect of orexin receptor (OXR) antagonists on reducing tolerance and dependence caused by drug abuse. Due to the significant growth of the studies on the orexinergic system, the current literature was conducted to collect the findings of previous studies on orexin and its receptors in the induction of drug addiction. In addition, cellular and molecular mechanismsof the possible role of orexin in drug tolerance and dependence are discussed. The findings indicate that the administration ofOXR antagonists reduces drug dependence. OXR blockers seem to counteract the addictive effects of drugs through multiple mechanisms, such as preventing neuronal adaptation. This review proposes the potential clinical use of OXR antagonists in the treatment of drug dependence.

Orexin, Hypocretin, Tolerance, dependence, withdrawal, Addiction