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 [5,19]. 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 [19]. 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 [13], and orexin neuron loss is associated with the human disorder [15-16]. 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 [2-3,7]. Small molecule orexin receptor antagonists have been shown to increase sleep across species, including man [4]. In 2014, suvorexant was the first orexin receptor antagonist approved for the treatment of insomnia [6]

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 [19]). 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 [9,12,20,23]. 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 [1,8,10,18,21].

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 [14,22,25]. Both orexin-A and -B have nearly equal affinity for OX₂ receptors (IC₅₀s of 38 and 36 nM, respectively [19]), and stimulate intracellular calcium levels through OX₂-mediated induction of G_q and phospholipase C activity, but are also capable of activating G_s, G_i, and potentially ion channels [9,11,17,20]. OX₂ receptors predominantly mediate the control of arousal induced by orexin neuropeptides, based on results from dog and rodents [4,13,24].

1. Abbas MG, Shoji H, Soya S, Hondo M, Miyakawa T, Sakurai T. (2015) Comprehensive Behavioral Analysis of Male Ox1r (-/-) Mice Showed Implication of Orexin Receptor-1 in Mood, Anxiety, and Social Behavior. Front Behav Neurosci, 9: 324. [PMID:26696848]

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]

3. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y et al.. (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell, 98 (4): 437-51. [PMID:10481909]

4. Chow M, Cao M. (2016) The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress. Nat Sci Sleep, 8: 81-6. [PMID:27051324]

5. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS et al.. (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl. Acad. Sci. U.S.A., 95 (1): 322-7. [PMID:9419374]

6. FDA. FDA approves new type of sleep drug, Belsomra. Accessed on 05/09/2016. Modified on 05/09/2016. FDA.gov, http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm

7. 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]

8. Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, Arch JR. (2000) A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul. Pept., 96 (1-2): 45-51. [PMID:11102651]

9. Holmqvist T, Akerman KE, Kukkonen JP. (2002) Orexin signaling in recombinant neuron-like cells. FEBS Lett., 526 (1-3): 11-4. [PMID:12208495]

10. 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]

11. Karteris E, Randeva HS, Grammatopoulos DK, Jaffe RB, Hillhouse EW. (2001) Expression and coupling characteristics of the CRH and orexin type 2 receptors in human fetal adrenals. J. Clin. Endocrinol. Metab., 86 (9): 4512-9. [PMID:11549701]

12. Kukkonen JP, Åkerman KEO. (2005) Intracellular Signal Pathways Utilized by the Hypocretin/Orexin Receptors. In Hypocretins. Integrators of Physiological Signals Edited by de Lecea L, Sutcliffe JG (Verlag: Springer) 221-231. [ISBN:9780387254463]

13. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E. (1999) The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell, 98 (3): 365-76. [PMID:10458611]

14. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK. (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J. Comp. Neurol., 435 (1): 6-25. [PMID:11370008]

15. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. (2000) Hypocretin (orexin) deficiency in human narcolepsy. Lancet, 355 (9197): 39-40. [PMID:10615891]

16. 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]

17. Randeva HS, Karteris E, Grammatopoulos D, Hillhouse EW. (2001) Expression of orexin-A and functional orexin type 2 receptors in the human adult adrenals: implications for adrenal function and energy homeostasis. J. Clin. Endocrinol. Metab., 86 (10): 4808-13. [PMID:11600545]

18. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, Upton N, Porter RA, Johns A, Blundell JE. (2001) SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. Eur. J. Neurosci., 13 (7): 1444-52. [PMID:11298806]

19. 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]

20. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F. (1999) Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR. Br. J. Pharmacol., 128 (1): 1-3. [PMID:10498827]

21. Steiner MA, Sciarretta C, Pasquali A, Jenck F. (2013) The selective orexin receptor 1 antagonist ACT-335827 in a rat model of diet-induced obesity associated with metabolic syndrome. Front Pharmacol, 4: 165. [PMID:24416020]

22. Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett, 438: 71-75. [PMID:9821961]

23. Turunen PM, Ekholm ME, Somerharju P, Kukkonen JP. (2010) Arachidonic acid release mediated by OX1 orexin receptors. Br. J. Pharmacol., 159 (1): 212-21. [PMID:20002100]

24. 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]

25. Wong KK, Ng SY, Lee LT, Ng HK, Chow BK. (2011) Orexins and their receptors from fish to mammals: a comparative approach. Gen. Comp. Endocrinol., 171 (2): 124-30. [PMID:21216246]