Orexin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Orexin receptors [10]) are activated by the endogenous polypeptides orexin-A (HCRT, O43612) and orexin-B (HCRT, O43612) (also known as hypocretin-1 and -2; 33 and 28 aa) derived from a common precursor, preproorexin or orexin precursor, by proteolytic cleavage and some typical peptide modifications [38]. Orexin signaling has been associated with regulation of sleep and wakefulness, reward and addiction, appetite and feeding, pain gating, stress response, anxiety and depression. Currently the orexin receptor ligands in clinical use are the dual orexin receptor antagonists suvorexant and lemborexant and daridorexant, which are used as hypnotics, and several dual and OX₂-selective antagonists are under development. Multiple orexin agonists are in development for the treatment of narcolepsy and other sleep disorders. Orexin receptor 3D structures have been solved [1,11-12,35,39,43-45].

The primary coupling of orexin receptors to G_q/11 proteins is rather speculative and based on the strong activation of phospholipase C, though recent studies in recombinant cells also stress the importance of G_q/11 [17]. Coupling of both receptors to G_i/o, G_s and and G_12/13 has also been reported [13,15,20,22,34]. For most native cellular responses observed, the G protein pathway is unknown. The relative potency order of endogenous ligands depends on the cellular signal transduction machinery [16]. Similarly, [Ala¹¹, D-Leu¹⁵]orexin-B, Nag 26 and YNT-185 may show variable selectivity for OX₂ receptors and may also activate OX₁ receptors [33,36,42]. Thorough characterization of many antagonists and radioligands has not been published, but the situation has recently improved for many commercially available ones. Among radioligands, [³H]SB-674042, [³H]EMPA, [³H]-almorexant, [¹²⁵I]orexin A (human, mouse, rat), [¹²⁵I]-orexin-B and [¹²⁵I][Ala¹¹, D-Leu¹⁵]orexin-B are commercially available. [³H]-TCS 1102, [³H]Cp-1 and Rhodamine Green-orexin-A [7] are also useful labelled tools. Orexin receptors have been reported to be able to form complexes with each other and some other GPCRs as well as σ1-receptors, which might affect the signaling and pharmacology [19,30]. Antagonists of the orexin receptors are the focus of major drug discovery efforts for their potential to treat insomnia and other disorders of wakefulness [37], while agonists would likely be useful in human narcolepsy [9,42].

* Key recommended reading is highlighted with an asterisk

Baimel C, Bartlett SE, Chiou LC, Lawrence AJ, Muschamp JW, Patkar O, Tung LW, Borgland SL. (2015) Orexin/hypocretin role in reward: implications for opioid and other addictions. Br J Pharmacol, 172 (2): 334-48. [PMID:24641197]

* Burdakov D. (2019) Reactive and predictive homeostasis: Roles of orexin/hypocretin neurons. Neuropharmacology, 154: 61-67. [PMID:30347195]

* Jacobson LH, Hoyer D, de Lecea L. (2022) Hypocretins (orexins): The ultimate translational neuropeptides. J Intern Med, 291 (5): 533-556. [PMID:35043499]

* James MH, Aston-Jones G. (2022) Orexin Reserve: A Mechanistic Framework for the Role of Orexins (Hypocretins) in Addiction. Biol Psychiatry, 92 (11): 836-844. [PMID:36328706]

Kukkonen JP. (2013) Physiology of the orexinergic/hypocretinergic system: a revisit in 2012. Am J Physiol, Cell Physiol, 304 (1): C2-32. [PMID:23034387]

* Kukkonen JP, Turunen PM. (2021) Cellular Signaling Mechanisms of Hypocretin/Orexin. Front Neurol Neurosci, 45: 91-102. [PMID:34052812]

Lebold TP, Bonaventure P, Shireman BT. (2013) Selective orexin receptor antagonists. Bioorg Med Chem Lett, 23 (17): 4761-9. [PMID:23891187]

* Sakurai T, Saito YC, Yanagisawa M. (2021) Interaction between Orexin Neurons and Monoaminergic Systems. Front Neurol Neurosci, 45: 11-21. [PMID:34052806]

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Subcommittee members: Jyrki P. Kukkonen Department of Pharmacology Faculty of Medicine University of Helsinki Helsinki Finland Daniel Hoyer Faculty of Medicine, Dentistry and Health Sciences School of Biomedical Sciences Department of Biochemistry and Pharmacology The University of Melbourne Parkville, Victoria 3010 Australia Gary Aston-Jones Rutgers University/Rutgers Biomedical & Health Sciences 259 SPH/RWJMS Research Building 683 Hoes Lane West Piscataway, NJ 08854 USA Pascal Bonaventure Janssen Research & Development 3210 Merryfield Row San Diego, CA 92121 USA Debbie Hartman Centessa Pharmaceuticals One Federal Street, 38th Floor Boston, MA 02110 USA Laura Jacobson Florey Institute of Neuroscience and Mental Health 30 Royal Parade Parkville, VIC 3052 Australia Terrence P. McDonald Merck and Co. 1770 Sumneytown Pike West Point, PA 19486 USA Takeshi Sakurai Faculty of Medicine/ International Institute for Integrative Sleep Medicine (WPI-IIIS) University of Tsukuba 1-1-1 Ten-no dai Tsukuba Ibaraki, 305-8575 Japan Masashi Yanagisawa Faculty of Medicine/ International Institute for Integrative Sleep Medicine (WPI-IIIS) University of Tsukuba 1-1-1 Ten-no dai Tsukuba Ibaraki, 305-8575 Japan