A review of the role of orexin system in pain modulation.

The roles of orexinergic system (orexin-A, orexin-B) and their receptors (orexin receptor type-1, orexin receptor type-2) in various physiological processes such as arousal, reward seeking behavior, energy homeostasis, sensory modulation, stress processing, cognition, endocrine functions, visceral functions and pain modulation have been established. This review summarizes the studies investigating orexin antinociceptive effects and their cellular mechanisms in various types of pain including neuropathic pain, migraine and cluster headache, visceral and orofacial pains. Moreover, the role of orexins in stress induced analgesia and on the development of morphine analgesic tolerance has been discussed. The antinociceptive effects of orexins have been shown in several pain models including thermal, mechanical and chemical induced nociception. Orexins modulate pain perception at both spinal and supraspinal levels. The periaqueductal gray (PAG) is one important supraspinal sites of orexin pain modulation. A possible involvement of endocannabinoids in supraspinal orexin-induced analgesia has been proposed. This review suggests a potential role of orexins in the management of pain.