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 [5,20]. 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 [20]. The name hypocretin reflects their hypothalamic expression and sequence similarity to the incretin peptide family [5]. While their effect on appetite is still controversial, and may be the result of increased arousal, orexins have a prominent role in promoting wakefulness and stabilizing vigilance state as demonstrated by pharmacological or genetic modulation of the orexin receptor signalling. Mutations in the OX₂ receptor are responsible for canine narcolepsy [15], and orexin neuron loss is associated with the human disorder [17-18]. 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 [2-3,8]. Small molecule orexin receptor antagonists have been shown to increase sleep across species, including man [4,21]. In 2014, suvorexant was the first orexin receptor antagonist approved for the treatment of insomnia [7].

OX₁

OX₁ receptors are G protein-coupled receptors whose orthologs are present throughout mammals [25]. In mammals, CNS expression includes brainstem nuclei involved in arousal and sleep/wake regulation as well as nuclei involved in reward signaling. Orexin-A and -B neuropeptides have different affinities for OX₁ receptors (IC₅₀s of 20 and 420 nM, respectively [20]). 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 [12-14,20]. OX₁ receptor signaling in sleep/wake regulation is not as well defined as for OX₂ receptors, but has been implicated in mood, anxiety, memory and reward, with mixed effects on feeding reported [1,9-11,19,22].

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 [6,16,23,25] . Both orexin-A and -B have nearly equal affinity for OX₂ receptors (IC₅₀s of 38 and 36 nM, respectively [20]), and elevate intracellular calcium levels through activation of G_q and phospholipase C activity, but the receptors are also capable of activating G_s, G_i, and potentially ion channels [12-14,20]. OX₂ receptors predominantly mediate the control of arousal induced by orexin neuropeptides, based on results from dog and rodents [15,21,24].

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8. 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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18. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, Nevsimalova S, Aldrich M, Reynolds D, Albin R et al.. (2000) A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med, 6 (9): 991-7. [PMID:10973318]

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20. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S et al.. (1998) Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell, 92 (4): 573-85. [PMID:9491897]

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