General
The orexins (orexin-A and orexin-B, also known as hypocretin-1 and hypocretin-2) are neuropeptides derived from a single precursor expressed in the posterior lateral and medial hypothalamus. These peptides were discovered independently by two different groups [6,23]. The name orexin (after orexis, Greek for appetite) was derived from experiments showing increased food intake after daytime intracerebral administration of the peptides in nocturnal rodents [23]. The name hypocretin reflects their hypothalamic expression and sequence similarity to the incretin peptide family [6]. Orexins act on two receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions and disturbances that include sleep-arousal, feeding-metabolism, reward-addiction, fear, anxiety, depression, pain gating and cognition [13].
Orexin receptors are G protein-coupled receptors whose orthologs are present throughout mammals [28]. Receptor activation results in elevated intracellular calcium levels mediated by G_q and phospholipase C activation, but contributions from G_s- and G_i-mediated regulation of cAMP levels as well as non-selective cation channels have also been described [16-18,23]. Orexins have a prominent role in promoting wakefulness and stabilizing vigilance state as demonstrated by pharmacological or genetic modulation of the orexin receptor signalling. Loss-of-function mutations in the OX₂ receptor are responsible for canine narcolepsy [19], and orexin neuron loss is associated with the human disorder [21-22]. Targeted mutagenesis of the gene encoding the orexin ligands, or genetically induced postnatal destruction of orexin-producing neurons in rodents results in a salient narcoleptic phenotype [2,4,10]. Small molecule orexin receptor antagonists (non-selective or OX₂-selective) have been shown to increase sleep across species, including man [5,24]. In 2014 suvorexant was the first orexin receptor antagonist approved for the treatment of insomnia [9], later followed by lemborexant and daridorexant.

OX₁
In mammals, CNS expression includes brainstem nuclei involved in arousal and sleep/wake regulation as well as nuclei involved in reward signaling [20,26]. Orexin-A and -B neuropeptides have different affinities for OX₁ receptors (IC₅₀s of 20 and 420 nM, respectively [23]). OX₁ receptor signaling in sleep/wake regulation is not as well defined as for OX₂ receptors, but has been particularly implicated in reward and addiction, with mixed effects on feeding reported [1,11,14-15,25,29].

OX₂
OX₂ receptors are found throughout vertebrates and, like OX₁ receptors, are expressed in brainstem and striatal nuclei, with additional expression in arousal-promoting histaminergic nuclei [7,20,26]. Both orexin-A and -B have nearly equal affinity for OX₂ receptors (IC₅₀s of 38 and 36 nM, respectively [23]). Based on results from dog, rodents and human, OX₂ receptors are predominantly responsible for the control of arousal and vigilance state stabilization mediated by orexin neuropeptides, and thus exogenous activation of OX₂ receptors increases wakefulness and reduces cataplexy in narcolepsy [3,8,12,19,24,27,29].

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2. Beuckmann CT, Sinton CM, Williams SC, Richardson JA, Hammer RE, Sakurai T, Yanagisawa M. (2004) Expression of a poly-glutamine-ataxin-3 transgene in orexin neurons induces narcolepsy-cataplexy in the rat. J Neurosci, 24 (18): 4469-77. [PMID:15128861]

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8. Evans R, Kimura H, Alexander R, Davies CH, Faessel H, Hartman DS, Ishikawa T, Ratti E, Shimizu K, Suzuki M et al.. (2022) Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients. Proc Natl Acad Sci U S A, 119 (35): e2207531119. [PMID:35994639]

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10. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, Sugiyama F, Yagami K, Goto K, Yanagisawa M et al.. (2001) Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron, 30 (2): 345-54. [PMID:11394998]

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

14. Johnson PL, Federici LM, Fitz SD, Renger JJ, Shireman B, Winrow CJ, Bonaventure P, Shekhar A. (2015) OREXIN 1 AND 2 RECEPTOR INVOLVEMENT IN CO2 -INDUCED PANIC-ASSOCIATED BEHAVIOR AND AUTONOMIC RESPONSES. Depress Anxiety, 32 (9): 671-83. [PMID:26332431]

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27. Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, Marcus JN, Lee C, Elmquist JK, Kohlmeier KA et al.. (2003) Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of Non-REM and REM sleep regulatory processes. Neuron, 38 (5): 715-30. [PMID:12797957]

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29. Yamamoto H, Nagumo Y, Ishikawa Y, Irukayama-Tomobe Y, Namekawa Y, Nemoto T, Tanaka H, Takahashi G, Tokuda A, Saitoh T et al.. (2022) OX2R-selective orexin agonism is sufficient to ameliorate cataplexy and sleep/wake fragmentation without inducing drug-seeking behavior in mouse model of narcolepsy. PLoS One, 17 (7): e0271901. [PMID:35867683]