BACKGROUND AND OBJECTIVE: Although opioid drugs cause analgesia and more effective in treatment of pain but, its utility is hindered by the development of tolerance to its analgesic effects. Orexin A and B (hypocretin 1 and 2) discovered in 1998 and projected to large areas of the brain regions involved in the tolerance and dependence to morphine. The attenuated withdrawal syndrome seen in orexinknock-out mice suggests that such regulation of orexin neurons may be an important contributor to morphine physical dependence and to the expression of withdrawal.

METHODS: This systematic review conducted on articles published on orexin from 1998 to 2012 in the following electronic databases: Medline, Pubmed, ISI and Scopus by using keywords including morphine, orexin, tolerance and dependence.

FINDINGS: Although morphine-tolerance tended to develop in response to repeated injections of morphine, pre-treatment of OXR1 antagonist prevented this effect, causing a delay in the development of morphine-tolerance. Moreover, co-administration of orexin receptor 1 antagonist with morphine significantly decreased the somatic signs of withdrawal.

CONCLUSION:This suggested development of orexin receptor antagonists could prevent the development of tolerance and dependence to morphine.