Orexin / Hypocretin

Orexin-A and orexin-B (also called hypocretin-1 and hypocretin-2) are two excitatory neuropeptides produced by a small population of neurons in the lateral and posterior hypothalamus, independently identified in 1998 by De Lecea and colleagues (as hypocretins, PNAS) and Sakurai and colleagues (as orexins, Cell). They act on two G-protein-coupled receptors (OX1R and OX2R) and project broadly to wake-promoting nuclei including the locus coeruleus, tuberomammillary nucleus, and basal forebrain. The system stabilises wakefulness and gates state transitions between wake, NREM, and REM sleep. Selective loss of orexin neurons - usually autoimmune - causes narcolepsy type 1 with cataplexy. Dual orexin receptor antagonists (DORAs), including suvorexant, lemborexant, and daridorexant, exploit this axis to treat chronic insomnia.