orexin

Orexins, also called hypocretins, are a pair of neuropeptides, orexin-A and orexin-B, produced by a small population of neurons in the lateral hypothalamus and nearby regions. They are derived from a common precursor protein, prepro-orexin, and are released to act on two G protein–coupled receptors, orexin receptor type 1 (OX1R) and type 2 (OX2R).

Although orexin neurons constitute a minority of hypothalamic cells, their axonal projections reach widespread brain regions involved in arousal, reward, and autonomic regulation, including the locus coeruleus, dorsal raphe, tuberomammillary nucleus, ventral tegmental area, and nucleus accumbens. Orexin signaling promotes wakefulness and stabilizes the sleep-wake cycle, enhances attention and response to salient stimuli, and influences feeding behavior and energy balance. It also modulates reward processing and stress responses, with broader effects on autonomic and endocrine systems.

Clinical relevance: loss of orexin-producing neurons or orexin deficiency is a central feature of narcolepsy type 1 (with cataplexy) in humans, leading to excessive daytime sleepiness and sudden sleep attacks. Measurements of orexin A in cerebrospinal fluid are markedly reduced or undetectable in many patients with narcolepsy type 1.

Pharmacology: orexin receptor antagonists, including dual OX1/2 inhibitors such as suvorexant and lemborexant, are approved for the treatment of insomnia, aiming to reduce wake-promoting signaling. Orexin signaling is also a target of ongoing research for obesity and other sleep-related disorders, while selective orexin agonists are being explored as potential therapies for narcolepsy and other disorders of excessive sleepiness.