orexins

Orexins, also called hypocretins, are neuropeptides produced primarily by a small population of neurons in the lateral hypothalamus. They consist of two peptides, orexin-A and orexin-B, derived from the precursor prepro-orexin, and they project widely throughout the brain. Orexins act on two G protein-coupled receptors, orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R).

Orexin signaling is involved in multiple physiological processes. The core function is promotion and stabilization of wakefulness and arousal, but orexins also regulate feeding and energy homeostasis, autonomic function, and reward-related pathways. Orexin neurons respond to metabolic state; they tend to be activated by energy deficit and inhibited by sleep. Receptors are located in key arousal centers such as the tuberomammillary nucleus, locus coeruleus, and ventral tegmental area, among others, enabling widespread influence on sleep–wake regulation and motivated behaviors.

Clinical significance is highlighted by the strong association between orexin dysfunction and narcolepsy type 1, in which loss of orexin-producing neurons leads to excessive daytime sleepiness and cataplexy. Animal models lacking orexin signaling exhibit narcolepsy-like symptoms, and alterations in the orexin system have been explored in obesity, addiction, and mood disorders. Because of their role in arousal, orexin pathways are attractive targets for therapeutics and are actively studied in various neuropsychiatric conditions.

Pharmacology includes dual orexin receptor antagonists (DORAs) such as suvorexant, lemborexant, and daridorexant, approved for insomnia in several regions. Selective orexin receptor antagonists and orexin agonists are under development for other sleep and metabolic disorders, reflecting ongoing interest in modulating this system for therapeutic benefit.

Discovery and history: Orexins were identified independently in 1998 by two groups—one naming the peptides orexin and the other hypocretin—leading to the dual terminology used in current literature.