Coregulation of sleep-pain physiological interplay by orexin system: An unprecedented review

• Orexinergic transmission regulates both nociception and arousal level. • Orexin receptors are expressed in both pain and sleep modulating centers. • Orexins promote analgesia and arousal through affecting shared neuronal mechanisms. • Induction of analgesia and wakefulness by orexin might favor survival during stress. • Imbalanced orexin level causes bidirectional dysregulation of sleep-pain processing. Accumulating evidence support the critical role of endogenous orexin system in modulation of various physiological functions. Among these, regulation of pain and wakefulness have extensively been investigated, however, by independent series of studies each focusing a distinct side. It is now well established that orexins induce potent analgesic effect via affecting their receptors within several specific brain structures. These mainly include locus coeruleus (LC), lateral paragigantocellularis (LPGi), ventral tegmental area (VTA), dorsal raphe nucleus (DRN), periaquiductal gray (PAG) and tuberomammillary nuclei (TMN). On the other hand, increased activity of orexinergic neurons enhances general wakefulness. Interestingly, a review of literature reveals that brain regions underlying orexin-mediated analgesia are most probably the site of action for orexin wake-promoting effects as well. The present study first pieces together the existing evidence supporting the rationale for the possibility of sleep-pain coregulation by orexin system and then suggests several shared mechanisms through which orexin can control the two mentioned processes. Furthermore, this study explains how imbalanced orexinergic transmission can cause progressive dysregulation of sleep-pain processing.