orexine

Orexin, also known as hypocretin, refers to two neuropeptides, orexin-A and orexin-B, produced by a small population of neurons in the lateral hypothalamus. They are derived from a common precursor, prepro-orexin, and project widely to many brain regions, including the cortex, brainstem, and thalamus.

Orexins promote wakefulness and arousal and help regulate appetite and energy expenditure. They activate arousal-promoting networks in the brain, interact with reward pathways, and influence autonomic functions such as feeding and metabolism.

They act on two G protein-coupled receptors, OX1R and OX2R. Orexin-A binds orexin receptors with higher affinity for OX1R, though both ligands activate both receptors; OX2R is particularly important for stabilizing wakefulness.

A loss or dysfunction of orexin neurons is a hallmark of narcolepsy type 1, with reduced CSF orexin-A levels; symptoms include excessive daytime sleepiness and cataplexy. The system is also studied for its roles in obesity, addiction, and stress responses.

Orexin receptor antagonists promote sleep by blunting wake-promoting orexin signaling and are approved for insomnia: suvorexant, lemborexant, and daridorexant. Orexin agonists are under development to treat narcolepsy and fatigue, but face delivery and safety challenges.

Discovery: Orexins were first described in 1998 by two groups; the names hypocretin (from hypothalamus + secretin-like) and orexin (orexis = appetite) both used; now orexin is common in English. The peptides are called orexin-A (hypocretin-1) and orexin-B (hypocretin-2).