The orexin story, sleep and sleep disturbances
Fabio Pizza, Lucie Barateau, Yves Dauvilliers, Giuseppe Plazzi
Abstract
The orexins, also known as hypocretins, are two neuropeptides (orexin A and B or hypocretin 1 and 2) produced by a few thousand neurons located in the lateral hypothalamus that were independently discovered by two research groups in 1998. Those two peptides bind two receptors (orexin/hypocretin receptor 1 and receptor 2) that are widely distributed in the brain and involved in the central physiological regulation of sleep and wakefulness, orexin receptor 2 having the major role in the maintenance of arousal. They are also implicated in a multiplicity of other functions, such as reward seeking, energy balance, autonomic regulation and emotional behaviours. The destruction of orexin neurons is responsible for the sleep disorder narcolepsy with cataplexy (type 1) in humans, and a defect of orexin signalling also causes a narcoleptic phenotype in several animal species. Orexin discovery is unprecedented in the history of sleep research, and pharmacological manipulations of orexin may have multiple therapeutic applications. Several orexin receptor antagonists were recently developed as new drugs for insomnia, and orexin agonists may be the next-generation drugs for narcolepsy. Given the broad range of functions of the orexin system, these drugs might also be beneficial for treating various conditions other than sleep disorders in the near future.