View source for Orexin

{{Short description|Neuropeptide that regulates arousal, wakefulness, and appetite}}
{{#invoke:Infobox_gene|getTemplateData|QID=Q22679768}}
'''Orexin''' ({{IPAc-en|ɒ|ˈ|r|ɛ|k|s|ɪ|n}}<!--source: OED-->), also known as '''hypocretin''', is a [[neuropeptide]] that regulates [[arousal]], [[wakefulness]], and [[appetite]].<ref name=Davis>{{ cite book | chapter = 24. Orexigenic Hypothalamic Peptides Behavior and Feeding - 24.5 Orexin |  chapter-url = https://books.google.com/books?id=KuAEPOPbW6MC&pg=PA361 | pages = 361–2 |vauthors=Davis JF, Choi DL, Benoit SC | title = Handbook of Behavior, Food and Nutrition |veditors=Preedy VR, Watson RR, Martin CR | publisher = Springer | year = 2011 | isbn = 978-0-387-92271-3 }}</ref> It exists in the forms of [[orexin-A]] and [[orexin-B]]. The most common form of [[narcolepsy]], type 1, in which the individual experiences brief losses of muscle tone ("drop attacks" or [[cataplexy]]), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.<ref name=Stanford>Stanford Center for Narcolepsy [http://med.stanford.edu/narcolepsy/faq1.html FAQ] (retrieved 27-Mar-2012)</ref><ref name="Sutcliffe">{{cite journal | vauthors = Sutcliffe JG, de Lecea L | title = The hypocretins: excitatory neuromodulatory peptides for multiple homeostatic systems, including sleep and feeding | journal = Journal of Neuroscience Research | volume = 62 | issue = 2 | pages = 161–168 | date = October 2000 | pmid = 11020209 | doi = 10.1002/1097-4547(20001015)62:2<161::AID-JNR1>3.0.CO;2-1 | s2cid = 33215844 }}</ref> 

There are 50,000–80,000 orexin-producing [[neurons]] in the human brain,<ref>{{cite journal | vauthors = Scammell TE, Winrow CJ | title = Orexin receptors: pharmacology and therapeutic opportunities | journal = Annual Review of Pharmacology and Toxicology | volume = 51 | pages = 243–266 | date = 2011-02-10 | pmid = 21034217 | pmc = 3058259 | doi = 10.1146/annurev-pharmtox-010510-100528 }}</ref> located predominantly in the perifornical area and [[lateral hypothalamus]].<ref name="Davis"/><ref name=Marcus/> They project widely throughout the [[central nervous system]], regulating wakefulness, feeding, and other behaviours.<ref name="Davis"/> There are two types of orexin [[peptide]] and two types of orexin [[receptor (biochemistry)|receptor]].<ref name="Boss"/><ref name=Marcus>{{ cite book | chapter = 3. Orexin Projections and Localization of Orexin Receptors |vauthors=Marcus JN, Elmquist JK | chapter-url = https://books.google.com/books?id=OHIu9l7bAmsC&pg=PA195 | page = 195 | title =  The Orexin/Hypocretin System: Physiology and Pathophysiology |veditors=Nishino S, Sakurai T | publisher = Springer | year = 2006 | isbn = 978-1-59259-950-9 }}</ref>

Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers working on the [[laboratory rat|rat]] [[brain]].<ref name="pmid9491897">{{cite journal | vauthors = Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, Williams SC, Richardson JA, Kozlowski GP, Wilson S, Arch JR, Buckingham RE, Haynes AC, Carr SA, Annan RS, McNulty DE, Liu WS, Terrett JA, Elshourbagy NA, Bergsma DJ, Yanagisawa M | display-authors = 6 | title = Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior | journal = Cell | volume = 92 | issue = 4 | pages = 573–585 | date = February 1998 | pmid = 9491897 | doi = 10.1016/S0092-8674(00)80949-6 | s2cid = 16294729 | doi-access = free }}</ref><ref name="pmid9419374">{{cite journal | vauthors = de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, Fukuhara C, Battenberg EL, Gautvik VT, Bartlett FS, Frankel WN, van den Pol AN, Bloom FE, Gautvik KM, Sutcliffe JG | display-authors = 6 | title = The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 1 | pages = 322–327 | date = January 1998 | pmid = 9419374 | pmc = 18213 | doi = 10.1073/pnas.95.1.322 | doi-access = free | bibcode = 1998PNAS...95..322D }}</ref><ref name=Extance>{{cite web |url=https://www.chemistryworld.com/features/the-brain-chemicals-that-control-what-we-enjoy/4016483.article |title=The brain chemicals that control what we enjoy | vauthors = Extance A |website=chemistryworld.com |publisher=[[Royal Society of Chemistry]] |date=2022-11-07 |access-date=2023-04-04 }}</ref> One group named it '''orexin''', from ''[[orexis]],'' meaning "appetite" in Greek; the other group named it '''hypocretin''', because it is produced in the ''hypo''thalamus and bears a weak resemblance to ''[[secretin]]'', another [[peptide]].<ref name=Stanford/> Officially, ''hypocretin'' (''HCRT'') is used to refer to the [[gene]]s and [[Primary transcript|transcripts]], while ''orexin'' is used to refer to the encoded [[peptide]]s.<ref name="pmid22759794">{{cite journal | vauthors = Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ | title = International Union of Basic and Clinical Pharmacology. LXXXVI. Orexin receptor function, nomenclature and pharmacology | journal = Pharmacological Reviews | volume = 64 | issue = 3 | pages = 389–420 | date = July 2012 | pmid = 22759794 | doi = 10.1124/pr.111.005546 | s2cid = 2038246 }}</ref> There is considerable similarity between the orexin system in the rat brain and that in the human brain.<ref name="Boss">{{cite journal | vauthors = Boss C, Roch C | title = Recent trends in orexin research--2010 to 2015 | journal = Bioorganic & Medicinal Chemistry Letters | volume = 25 | issue = 15 | pages = 2875–2887 | date = August 2015 | pmid = 26045032 | doi = 10.1016/j.bmcl.2015.05.012 }}</ref>

== Discovery ==
In 1998, reports of the discovery of orexin/hypocretin were published nearly simultaneously. Luis de Lecea, [[Thomas Kilduff]], and colleagues reported the discovery of the hypocretin system at the same time as Takeshi Sakurai from [[Masashi Yanagisawa]]'s lab at the [[University of Texas Southwestern Medical Center at Dallas]] reported the discovery of the ''orexins'' to reflect the orexigenic (appetite-stimulating) activity of these peptides. In their 1998 paper describing these neuropeptides, they also reported discovery of two orexin receptors, dubbed [[Orexin receptor type 1]] (OX<sub>1</sub>R or OX1) and [[Orexin receptor type 2]] (OX<sub>2</sub>R or OX2).<ref name="pmid9491897"/>  Masashi Yanagisawa and Emmanuel Mignot were awarded the Breakthrough Prize in 2022 for this discovery.

The two groups also took different approaches towards their discovery. One team was interested in finding new genes that were expressed in the hypothalamus. In 1996, scientists from the [[Scripps Research Institute]] reported the discovery of several genes in the rat brain, including one they dubbed "clone 35." Their work showed that clone 35 expression was limited to the lateral hypothalamus.<ref name="pmid8710940">{{cite journal | vauthors = Gautvik KM, de Lecea L, Gautvik VT, Danielson PE, Tranque P, Dopazo A, Bloom FE, Sutcliffe JG | display-authors = 6 | title = Overview of the most prevalent hypothalamus-specific mRNAs, as identified by directional tag PCR subtraction | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 93 | issue = 16 | pages = 8733–8738 | date = August 1996 | pmid = 8710940 | pmc = 38742 | doi = 10.1073/pnas.93.16.8733 | doi-access = free | bibcode = 1996PNAS...93.8733G }}</ref> They extracted selective DNA found in the lateral hypothalamus. They cloned this DNA and studied it using electron microscopy. Neurotransmitters found in this area were oddly similar to the gut hormone, secretin, a member of the [[incretin]] family, so they named hypocretin to stand for a hypothalamic member of the incretin family.<ref>{{cite journal | vauthors = Ebrahim IO, Howard RS, Kopelman MD, Sharief MK, Williams AJ | title = The hypocretin/orexin system | journal = Journal of the Royal Society of Medicine | volume = 95 | issue = 5 | pages = 227–230 | date = May 2002 | pmid = 11983761 | pmc = 1279673 | doi = 10.1177/014107680209500503 }}</ref> These cells were first thought to reside and work only within the lateral hypothalamus area, but immunocytochemistry techniques revealed the various projections this area truly had to other parts of the brain. A majority of these projections reached the [[limbic system]] and structures associated with it (including the amygdala, septum, and basal forebrain area).

On the other hand, Sakurai and colleagues were studying the orexin system as [[orphan receptor]]s. To this end, they used transgenic cell lines that expressed individual orphan receptors and then exposed them to different potential ligands. They found that the orexin peptides activated the cells expressing the orexin receptors and went on to find orexin peptide expression specifically in the hypothalamus. Additionally, when either orexin peptide was administered to rats it stimulated feeding, giving rise to the name 'orexin'.<ref name="pmid9491897"/>

The nomenclature of the orexin/hypocretin system now recognizes the history of its discovery. "Hypocretin" refers to the gene or genetic products and "orexin" refers to the protein, reflecting the differing approaches that resulted in its discovery.<ref name=Extance/> The use of both terms is also a practical necessity because "HCRT" is the standard gene symbol in databases like [[GenBank]] and "OX" is used to refer to the pharmacology of the peptide system by the [[International Union of Basic and Clinical Pharmacology]].<ref name="pmid22759794"/>

== Isoforms ==
There are two types of orexin: [[orexin-A]] and [[orexin-B]] (hypocretin-1 and hypocretin-2).<ref name="iso"/><ref name="mogavero 2023">{{Cite journal |vauthors=Mogavero MP, Silvani A, Lanza G, DelRosso LM, Ferini-Strambi L, Ferri R |date=2023-01-22 |title=Targeting Orexin Receptors for the Treatment of Insomnia: From Physiological Mechanisms to Current Clinical Evidence and Recommendations |journal=[[Nature and Science of Sleep]] |type=Review |language=English |volume=15 |pages=17–38 |doi=10.2147/NSS.S201994 |pmc=9879039 |pmid=36713640 |doi-access=free}}</ref> They are excitatory [[neuropeptide]]s with approximately 50% sequence identity, produced by cleavage of a single precursor protein.<ref name="iso"/> This precursor protein is known as '''prepro-orexin''' (or '''preprohypocretin''') and is a 130 [[amino acid]] [[pre-pro-peptide]] encoded by the [[gene]] ''HRCT'' and located on [[chromosome 17]] (17q21).<ref name="Nakamachi2021">{{cite book | title = Handbook of Hormones | edition = 2 | vauthors = Nakamachi T | chapter = Orexin | date = 2021 | pages = 133–135 | publisher = Elsevier | doi = 10.1016/B978-0-12-820649-2.00036-X | isbn = 978-0-12-820649-2 | s2cid = 243394088 | url = }}</ref> Orexin-A is 33 amino acid residues long and has two intrachain [[disulfide bond]]s; orexin-B is a linear 28 amino acid residue peptide.<ref name="iso">{{cite journal | vauthors = Inutsuka A, Yamanaka A | title = The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions | journal = Frontiers in Endocrinology | volume = 4 | page = 18 | year = 2013 | pmid = 23508038 | pmc = 3589707 | doi = 10.3389/fendo.2013.00018 | doi-access = free }}</ref> Although these peptides are produced by a very small population of cells in the lateral and posterior [[hypothalamus]], they send projections throughout the brain.  The orexin peptides bind to the two [[G-protein coupled receptor|G-protein coupled]] [[orexin receptor]]s, [[Hypocretin (orexin) receptor 1|OX<sub>1</sub>]] and [[Hypocretin (orexin) receptor 2|OX<sub>2</sub>]], with orexin-A binding to both OX<sub>1</sub> and OX<sub>2</sub> with approximately equal affinity while orexin-B binds mainly to OX<sub>2</sub> and is 5&nbsp;times less potent at OX<sub>1</sub>.<ref name="pmid14691055">{{cite journal | vauthors = Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ | title = Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor | journal = British Journal of Pharmacology | volume = 141 | issue = 2 | pages = 340–346 | date = January 2004 | pmid = 14691055 | pmc = 1574197 | doi = 10.1038/sj.bjp.0705610 }}</ref><ref name="pmid10498827">{{cite journal | vauthors = Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, Elshourbagy NA, Ellis CE, Middlemiss DN, Brown F | display-authors = 6 | title = Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR | journal = British Journal of Pharmacology | volume = 128 | issue = 1 | pages = 1–3 | date = September 1999 | pmid = 10498827 | pmc = 1571615 | doi = 10.1038/sj.bjp.0702780 }}</ref>

The orexins are strongly conserved peptides, found in all major classes of vertebrates.<ref>{{cite journal | vauthors = Wong KK, Ng SY, Lee LT, Ng HK, Chow BK | title = Orexins and their receptors from fish to mammals: a comparative approach | journal = General and Comparative Endocrinology | volume = 171 | issue = 2 | pages = 124–130 | date = April 2011 | pmid = 21216246 | doi = 10.1016/j.ygcen.2011.01.001 }}</ref>

== Function ==
{{See also|Orexinergic projection system}}
The orexin system was initially suggested to be primarily involved in the stimulation of food intake, based on the finding that central administration of orexin-A and -B increased food intake. In addition, it stimulates wakefulness, regulates [[energy (psychological)|energy]] expenditure, and modulates visceral function. The orexin system has been hypothesized to function by exciting other neurons that produce neurotransmitters (such as the locus coeruleus), as well as by inhibiting neurons in the [[ventrolateral preoptic nucleus]], which is a region of the brain whose neuronal activity is imperative to proper sleep function.<ref>{{cite journal | vauthors = Kawashima S, Lou F, Kusumoto-Yoshida I, Hao L, Kuwaki T | title = Activation of the rostral nucleus accumbens shell by optogenetics induces cataplexy-like behavior in orexin neuron-ablated mice | journal = Scientific Reports | volume = 13 | issue = 1 | article-number = 2546 | date = February 2023 | pmid = 36781929 | pmc = 9925750 | doi = 10.1038/s41598-023-29488-x }}</ref>

=== Brown fat activation ===
Many studies support that the orexin neurons regulate [[brown adipose tissue]] (BAT) activity via the sympathetic nervous system to enhance energy expenditure.<ref name="pmid27524625 ">{{cite journal | vauthors = Martins L, Seoane-Collazo P, Contreras C, González-García I, Martínez-Sánchez N, González F, Zalvide J, Gallego R, Diéguez C, Nogueiras R, Tena-Sempere M, López M | display-authors = 6 | title = A Functional Link between AMPK and Orexin Mediates the Effect of BMP8B on Energy Balance | journal = Cell Reports | volume = 16 | issue = 8 | pages = 2231–2242 | date = August 2016 | pmid = 27524625 | pmc = 4999418 | doi = 10.1016/j.celrep.2016.07.045 }}</ref><ref name="pmid22049437">{{cite journal | vauthors = Tupone D, Madden CJ, Cano G, Morrison SF | title = An orexinergic projection from perifornical hypothalamus to raphe pallidus increases rat brown adipose tissue thermogenesis | journal = The Journal of Neuroscience | volume = 31 | issue = 44 | pages = 15944–15955 | date = November 2011 | pmid = 22049437 | pmc = 3224674 | doi = 10.1523/JNEUROSCI.3909-11.2011 }}</ref>
Although orexin [[knockout mice]] were reported to show maldevelopment of [[brown adipose tissue]] (BAT),<ref name="pmid21982708">{{cite journal | vauthors = Sellayah D, Bharaj P, Sikder D | title = Orexin is required for brown adipose tissue development, differentiation, and function | journal = Cell Metabolism | volume = 14 | issue = 4 | pages = 478–490 | date = October 2011 | pmid = 21982708 | doi = 10.1016/j.cmet.2011.08.010 | doi-access = free }}</ref> subsequent report has shown normal development of BAT.<ref name="pmid31546102">{{cite journal | vauthors = Kakizaki M, Tsuneoka Y, Takase K, Kim SJ, Choi J, Ikkyu A, Abe M, Sakimura K, Yanagisawa M, Funato H | display-authors = 6 | title = Differential Roles of Each Orexin Receptor Signaling in Obesity | journal = iScience | volume = 20 | pages = 1–13 | date = October 2019 | pmid = 31546102 | pmc = 6817686 | doi = 10.1016/j.isci.2019.09.003 | bibcode = 2019iSci...20....1K }}</ref>

=== Wakefulness ===
Orexin seems to promote [[wakefulness]]. Studies indicate that a major role of the orexin system is to integrate metabolic, circadian and [[sleep debt]] influences to determine whether an animal should be asleep, or awake and active. Orexin neurons strongly excite various brain nuclei with important roles in wakefulness including the [[dopamine]], [[norepinephrine]], [[histamine]] and [[acetylcholine]] systems<ref name="pmid9614245">{{cite journal | vauthors = Sherin JE, Elmquist JK, Torrealba F, Saper CB | title = Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat | journal = The Journal of Neuroscience | volume = 18 | issue = 12 | pages = 4705–4721 | date = June 1998 | pmid = 9614245 | pmc = 6792696 | doi = 10.1523/JNEUROSCI.18-12-04705.1998 }}</ref><ref name="pmid12040064">{{cite journal | vauthors = Lu J, Bjorkum AA, Xu M, Gaus SE, Shiromani PJ, Saper CB | title = Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep | journal = The Journal of Neuroscience | volume = 22 | issue = 11 | pages = 4568–4576 | date = June 2002 | pmid = 12040064 | pmc = 6758802 | doi = <!-- 20026455 --> }}</ref> and appear to play an important role in stabilizing wakefulness and sleep.

The discovery that an orexin receptor mutation causes the [[sleep disorder]] canine [[narcolepsy]]<ref name="pmid10458611">{{cite journal | vauthors = Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, Qiu X, de Jong PJ, Nishino S, Mignot E | display-authors = 6 | title = The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene | journal = Cell | volume = 98 | issue = 3 | pages = 365–376 | date = August 1999 | pmid = 10458611 | doi = 10.1016/S0092-8674(00)81965-0 | s2cid = 902666 | doi-access = free }}</ref> in [[Doberman Pinscher]]s  subsequently indicated a major role for this system in [[sleep]] regulation. Genetic knockout mice lacking the gene for orexin were also reported to exhibit narcolepsy.<ref name="pmid10481909">{{cite journal | vauthors = Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, Richardson JA, Williams SC, Xiong Y, Kisanuki Y, Fitch TE, Nakazato M, Hammer RE, Saper CB, Yanagisawa M | display-authors = 6 | title = Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation | journal = Cell | volume = 98 | issue = 4 | pages = 437–451 | date = August 1999 | pmid = 10481909 | doi = 10.1016/S0092-8674(00)81973-X | s2cid = 89799178 | doi-access = free }}</ref> Transitioning frequently and rapidly between sleep and wakefulness, these mice display many of the symptoms of narcolepsy.  Researchers are using this animal model of narcolepsy to study the disease.<ref name="pmid15254084">{{cite journal | vauthors = Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE | title = Behavioral state instability in orexin knock-out mice | journal = The Journal of Neuroscience | volume = 24 | issue = 28 | pages = 6291–6300 | date = July 2004 | pmid = 15254084 | pmc = 6729542 | doi = 10.1523/JNEUROSCI.0586-04.2004 }}</ref> Narcolepsy results in [[excessive daytime sleepiness]], inability to consolidate wakefulness in the day (and sleep at night), and [[cataplexy]], which is the loss of muscle tone in response to strong, usually positive, emotions. Dogs that lack a functional receptor for orexin have narcolepsy, while animals and people lacking the orexin neuropeptide itself also have narcolepsy. Organisms with narcolepsy were also found to experience REM sleep at any time of day, suggesting an alteration of function of  REM sleep which can lead to [[Hypnagogia|hypnagogic]] hallucinations.<ref>{{cite journal | vauthors = Scammell TE, Winrow CJ | title = Orexin receptors: pharmacology and therapeutic opportunities | journal = Annual Review of Pharmacology and Toxicology | volume = 51 | pages = 243–266 | date = 2011-02-10 | pmid = 21034217 | pmc = 3058259 | doi = 10.1146/annurev-pharmtox-010510-100528 }}</ref>

Central administration of orexin-A strongly promotes wakefulness, increases body temperature and locomotion, and elicits a strong increase in energy expenditure. [[Sleep deprivation]] also increases orexin-A transmission. The orexin system may thus be more important in the regulation of energy expenditure than in the regulation of food intake. In fact, orexin-deficient people with narcolepsy have increased obesity rather than decreased [[Body mass index|BMI]], as would be expected if orexin were primarily an appetite stimulating peptide. Another indication that deficits of orexin cause narcolepsy is that depriving monkeys of sleep for 30–36&nbsp;hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.<ref>{{cite magazine |author=Alexis Madrigal |author-link=Alexis Madrigal |date=2007-12-28 |title=Snorting a Brain Chemical Could Replace Sleep |url=https://www.wired.com/science/discoveries/news/2007/12/sleep_deprivation |archive-url=https://web.archive.org/web/20100210154949/https://www.wired.com/science/discoveries/news/2007/12/sleep_deprivation |archive-date=2010-02-10 |access-date=2008-02-05 |magazine=Wired |publisher=Wired News, Condé Nast}}</ref><ref name="pmid18160631">{{cite journal | vauthors = Deadwyler SA, Porrino L, Siegel JM, Hampson RE | title = Systemic and nasal delivery of orexin-A (Hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates | journal = The Journal of Neuroscience | volume = 27 | issue = 52 | pages = 14239–14247 | date = December 2007 | pmid = 18160631 | pmc = 6673447 | doi = 10.1523/JNEUROSCI.3878-07.2007 }}</ref>

In humans, narcolepsy is associated with a specific variant of the [[human leukocyte antigen]] (HLA) complex.<ref name="pmid10984567">{{cite journal | vauthors = Klein J, Sato A | title = The HLA system. Second of two parts | journal = The New England Journal of Medicine | volume = 343 | issue = 11 | pages = 782–786 | date = September 2000 | pmid = 10984567 | doi = 10.1056/NEJM200009143431106 }}</ref> Furthermore, genome-wide analysis shows that, in addition to the HLA variant, people with narcolepsy also exhibit a specific genetic [[mutation]] in the [[T cell|T-cell]] [[T cell receptor|receptor]] alpha locus.<ref name="pmid19412176">{{cite journal | vauthors = Hallmayer J, Faraco J, Lin L, Hesselson S, Winkelmann J, Kawashima M, Mayer G, Plazzi G, Nevsimalova S, Bourgin P, Hong SC, Honda Y, Honda M, Högl B, Longstreth WT, Montplaisir J, Kemlink D, Einen M, Chen J, Musone SL, Akana M, Miyagawa T, Duan J, Desautels A, Erhardt C, Hesla PE, Poli F, Frauscher B, Jeong JH, Lee SP, Ton TG, Kvale M, Kolesar L, Dobrovolná M, Nepom GT, Salomon D, Wichmann HE, Rouleau GA, Gieger C, Levinson DF, Gejman PV, Meitinger T, Young T, Peppard P, Tokunaga K, Kwok PY, Risch N, Mignot E | display-authors = 6 | title = Narcolepsy is strongly associated with the T-cell receptor alpha locus | journal = Nature Genetics | volume = 41 | issue = 6 | pages = 708–711 | date = June 2009 | pmid = 19412176 | pmc = 2803042 | doi = 10.1038/ng.372 }}</ref> In conjunction, these genetic anomalies cause the immune system to attack and kill the critical orexin neurons. Hence the absence of orexin-producing [[neuron]]s in people with narcolepsy may be the result of an [[autoimmunity|autoimmune]] disorder.<ref name="url_eurekalert">{{cite web | url = http://www.eurekalert.org/pub_releases/2009-05/sumc-nia042809.php | title = Narcolepsy is an autoimmune disorder, Stanford researcher says | date = 2009-05-03 | work = EurekAlert | publisher = American Association for the Advancement of Science | access-date = 2009-05-31 | archive-date = 2009-05-10 | archive-url = https://web.archive.org/web/20090510122328/http://www.eurekalert.org/pub_releases/2009-05/sumc-nia042809.php }}</ref>

=== Food intake ===
Orexin increases the craving for food, and correlates with the function of the substances that promote its production. Orexin is also shown to increase meal size by suppressing inhibitory postingestive feedback.<ref>{{cite journal | vauthors = Baird JP, Choe A, Loveland JL, Beck J, Mahoney CE, Lord JS, Grigg LA | title = Orexin-A hyperphagia: hindbrain participation in consummatory feeding responses | journal = Endocrinology | volume = 150 | issue = 3 | pages = 1202–1216 | date = March 2009 | pmid = 19008313 | pmc = 2654731 | doi = 10.1210/en.2008-0293 }}</ref> However, some studies suggest that the stimulatory effects of orexin on feeding may be due to general arousal without necessarily increasing overall food intake.<ref>{{cite journal | vauthors = Ida T, Nakahara K, Katayama T, Murakami N, Nakazato M | title = Effect of lateral cerebroventricular injection of the appetite-stimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats | journal = Brain Research | volume = 821 | issue = 2 | pages = 526–529 | date = March 1999 | pmid = 10064841 | doi = 10.1016/S0006-8993(99)01131-2 | s2cid = 39775146 }}</ref>

Review findings suggest that [[hyperglycemia]] that occurs in mice due to a habitual high-fat diet leads to a reduction in signalling by orexin receptor-2, and that orexin receptors may be a future therapeutic target.<ref name="Tsuneki">{{cite journal | vauthors = Tsuneki H, Wada T, Sasaoka T | title = Role of orexin in the regulation of glucose homeostasis | journal = Acta Physiologica | volume = 198 | issue = 3 | pages = 335–348 | date = March 2010 | pmid = 19489767 | doi = 10.1111/j.1748-1716.2009.02008.x | s2cid = 23346403 }}</ref> [[Leptin]] is a hormone produced by fat cells and acts as a long-term internal measure of energy state. [[Ghrelin]] is a short-term factor secreted by the stomach just before an expected meal, and strongly promotes food intake. Orexin-producing cells have been shown to be inhibited by leptin (through the leptin receptor pathway), but are activated by ghrelin and [[hypoglycemia]] ([[glucose]] inhibits orexin production). Orexin, as of 2007, is claimed to be a very important link between metabolism and sleep regulation.<ref>{{cite journal | vauthors = Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, van Gerven J, de Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F | display-authors = 6 | title = Promotion of sleep by targeting the orexin system in rats, dogs and humans | journal = Nature Medicine | volume = 13 | issue = 2 | pages = 150–155 | date = February 2007 | pmid = 17259994 | doi = 10.1038/nm1544 | s2cid = 40999737 }}</ref><ref>{{cite journal | vauthors = Sakurai T | title = The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness | journal = Nature Reviews. Neuroscience | volume = 8 | issue = 3 | pages = 171–181 | date = March 2007 | pmid = 17299454 | doi = 10.1038/nrn2092 | s2cid = 8932862 }}</ref> Such a relationship has been long suspected, based on the observation that long-term sleep deprivation in rodents dramatically increases food intake and energy metabolism, i.e., [[catabolism]], with lethal consequences on a long-term basis. Sleep deprivation then leads to a lack of energy. In order to make up for this lack of energy, many people use high-carbohydrate and high-fat foods that ultimately can lead to poor health and weight gain. Other dietary nutrients, amino acids, also can activate orexin neurons, and they can suppress the glucose response of orexin neurons at physiological concentration, causing the energy balance that orexin maintains to be thrown off its normal cycle.<ref>{{cite journal | vauthors = Inutsuka A, Yamanaka A | title = The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions | journal = Frontiers in Endocrinology | volume = 4 | issue = 18 | page = 18 | date = 2013-03-06 | pmid = 23508038 | pmc = 3589707 | doi = 10.3389/fendo.2013.00018 | doi-access = free }}</ref>

=== Addiction ===
Preliminary research shows potential for orexin blockers in the treatment of cocaine, opioid, and [[alcoholism|alcohol]] addiction.<ref>{{Cite news|url=https://www.sciencedaily.com/releases/2005/08/050827140339.htm|title=Neurotransmitter Orexin Associated With Pleasure And Reward Pathways In The Brain|work=ScienceDaily|access-date=2018-05-08 }}</ref><ref>{{cite journal | vauthors = Harris GC, Wimmer M, Aston-Jones G | title = A role for lateral hypothalamic orexin neurons in reward seeking | journal = Nature | volume = 437 | issue = 7058 | pages = 556–559 | date = September 2005 | pmid = 16100511 | doi = 10.1038/nature04071 | s2cid = 4386257 | doi-access = free | bibcode = 2005Natur.437..556H }}</ref><ref>{{cite journal | vauthors = Smith RJ, See RE, Aston-Jones G | title = Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking | journal = The European Journal of Neuroscience | volume = 30 | issue = 3 | pages = 493–503 | date = August 2009 | pmid = 19656173 | pmc = 2771107 | doi = 10.1111/j.1460-9568.2009.06844.x }}</ref> For example, [[Brown rat|lab rats]] given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.<ref>{{cite news | url = http://www.worldcampaign.net/forum/view.php?id=1707 | author = Helen Puttick | title = Hope in fight against alcoholism | date = 2006-12-26 | publisher = [[The Herald (Glasgow)|The Herald]] | access-date = 2007-02-11 | archive-url = https://web.archive.org/web/20120210214128/http://www.worldcampaign.net/forum/view.php?id=1707 | archive-date = 2012-02-10 }}</ref><ref name="pmid16751790">{{cite journal | vauthors = Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B | title = The orexin system regulates alcohol-seeking in rats | journal = British Journal of Pharmacology | volume = 148 | issue = 6 | pages = 752–759 | date = July 2006 | pmid = 16751790 | pmc = 1617074 | doi = 10.1038/sj.bjp.0706789 }}</ref> Wild type mice that were treated with morphine were found to be at a higher risk of developing addiction when compared to mice that did not produce orexin.<ref>{{cite journal | vauthors = Chieffi S, Carotenuto M, Monda V, Valenzano A, Villano I, Precenzano F, Tafuri D, Salerno M, Filippi N, Nuccio F, Ruberto M, De Luca V, Cipolloni L, Cibelli G, Mollica MP, Iacono D, Nigro E, Monda M, Messina G, Messina A | display-authors = 6 | title = Orexin System: The Key for a Healthy Life | journal = Frontiers in Physiology | volume = 8 | article-number = 357 | date = 2017-05-31 | pmid = 28620314 | pmc = 5450021 | doi = 10.3389/fphys.2017.00357 | doi-access = free }}</ref>

Studies of orexin involvement in nicotine addiction have had mixed results. For example, blocking the orexin-1 receptor with the selective [[orexin antagonist]] [[SB-334,867]] reduced nicotine [[self-administration]] in rats and that smokers who sustained damage to the [[Insular cortex|insula]], a brain region that regulates cravings and contains orexin-1 receptors, lost the desire to smoke.<ref name="urlBlocking A Neuropeptide Receptor Decreases Nicotine Addiction">{{cite web | url = https://www.sciencedaily.com/releases/2008/11/081124174851.htm | title = Blocking A Neuropeptide Receptor Decreases Nicotine Addiction | date = 2008-12-01 | publisher = ScienceDaily LLC | access-date = 2009-02-11}}</ref> However, other studies in rats using the dual orexin receptor antagonist TCS 1102 have not found similar effects.<ref>{{cite journal | vauthors = Khoo SY, McNally GP, Clemens KJ | title = The dual orexin receptor antagonist TCS1102 does not affect reinstatement of nicotine-seeking | journal = PLOS ONE | volume = 12 | issue = 3 | article-number = e0173967 | date = 2017 | pmid = 28296947 | pmc = 5351999 | doi = 10.1371/journal.pone.0173967 | doi-access = free | bibcode = 2017PLoSO..1273967K }}</ref>

=== Lipid metabolism ===
Orexin-A (OXA) has been demonstrated to have a direct effect on an aspect of [[lipid]] metabolism. OXA stimulates [[glucose]] uptake in [[3T3-L1]] [[adipocytes]] and that increased energy uptake is stored as lipids ([[triacylglycerol]]). OXA thus increases [[lipogenesis]]. It also inhibits [[lipolysis]] and stimulates the secretion of [[adiponectin]]. These effects are thought to be mostly conferred via the [[PI3K]] pathway because this pathway inhibitor (LY294002) completely blocks OXA effects in adipocytes.<ref>{{cite journal | vauthors = Skrzypski M, T Le T, Kaczmarek P, Pruszynska-Oszmalek E, Pietrzak P, Szczepankiewicz D, Kolodziejski PA, Sassek M, Arafat A, Wiedenmann B, Nowak KW, Strowski MZ | display-authors = 6 | title = Orexin A stimulates glucose uptake, lipid accumulation and adiponectin secretion from 3T3-L1 adipocytes and isolated primary rat adipocytes | journal = Diabetologia | volume = 54 | issue = 7 | pages = 1841–1852 | date = July 2011 | pmid = 21505958 | doi = 10.1007/s00125-011-2152-2 | doi-access = free }}</ref> The link between OXA and lipid metabolism is  currently being studied.

=== Mood ===
High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.<ref name="happiness">{{cite journal | vauthors = Blouin AM, Fried I, Wilson CL, Staba RJ, Behnke EJ, Lam HA, Maidment NT, Karlsson KÆ, Lapierre JL, Siegel JM | display-authors = 6 | title = Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction | journal = Nature Communications | volume = 4 | article-number = 1547 | year = 2013 | pmid = 23462990 | pmc = 3595130 | doi = 10.1038/ncomms2461 | bibcode = 2013NatCo...4.1547B }} 
*{{lay source |template = cite press release|url = https://www.sciencedaily.com/releases/2013/03/130307145720.htm|title = Is this peptide a key to happiness? Findings suggests possible new treatment for depression, other disorders|date = March 7, 2013 |website = Science Daily}}</ref> The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression. Orexins have also been hypothesized to aid in the development of resilience to the stress response, as their activity in the [[ventral pallidum]] was found to decrease depressive symptoms by activating GABAergic neurons at that site.<ref>{{cite journal | vauthors = Ji MJ, Zhang XY, Chen Z, Wang JJ, Zhu JN | title = Orexin prevents depressive-like behavior by promoting stress resilience | journal = Molecular Psychiatry | volume = 24 | issue = 2 | pages = 282–293 | date = February 2019 | pmid = 30087452 | pmc = 6755988 | doi = 10.1038/s41380-018-0127-0 }}</ref>

It has been observed that orexin, while implicated in addiction and depression, is also involved in the display of [[anhedonia]] in ADHD. Proper functioning of orexin has been shown to have a large degree of control over behaviors that are motivated by a need to survive, such as searching for food when an organism is starving. When orexin does not function as intended, it impairs an organism's ability to feel pleasure from strongly motivated actions.<ref>{{cite journal | vauthors = Katzman MA, Katzman MP | title = Neurobiology of the Orexin System and Its Potential Role in the Regulation of Hedonic Tone | journal = Brain Sciences | volume = 12 | issue = 2 | page = 150 | date = January 2022 | pmid = 35203914 | pmc = 8870430 | doi = 10.3390/brainsci12020150 | doi-access = free }}</ref>

== Orexin neurons ==
===Neurotransmitters===
Orexinergic neurons have been shown to be sensitive to inputs from Group III [[metabotropic glutamate receptors]],<ref name="pmid15044540">{{cite journal | vauthors = Acuna-Goycolea C, Li Y, Van Den Pol AN | title = Group III metabotropic glutamate receptors maintain tonic inhibition of excitatory synaptic input to hypocretin/orexin neurons | journal = The Journal of Neuroscience | volume = 24 | issue = 12 | pages = 3013–3022 | date = March 2004 | pmid = 15044540 | pmc = 6729849 | doi = 10.1523/JNEUROSCI.5416-03.2004 }}</ref> [[cannabinoid receptor 1]] and {{abbr|CB1–OX1|cannabinoid-1 and orexin-1}} [[GPCR oligomer|receptor heterodimers]],<ref name="Cannabinoid-Orexin systemic cross-talk">{{cite journal | vauthors = Flores A, Maldonado R, Berrendero F | title = Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far | journal = Frontiers in Neuroscience | volume = 7 | page = 256 | date = December 2013 | pmid = 24391536 | pmc = 3868890 | doi = 10.3389/fnins.2013.00256 | quote = Direct CB1-HcrtR1 interaction was first proposed in 2003 (Hilairet et al., 2003). Indeed, a 100-fold increase in the potency of hypocretin-1 to activate the ERK signaling was observed when CB1 and HcrtR1 were co-expressed&nbsp;...  In this study, a higher potency of hypocretin-1 to regulate CB1-HcrtR1 heteromer compared with the HcrtR1-HcrtR1 homomer was reported (Ward et al., 2011b). These data provide unambiguous identification of CB1-HcrtR1 heteromerization, which has a substantial functional impact.&nbsp;... The existence of a cross-talk between the hypocretinergic and endocannabinoid systems is strongly supported by their partially overlapping anatomical distribution and common role in several physiological and pathological processes. However, little is known about the mechanisms underlying this interaction. | doi-access = free }}<br />{{bull}}[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868890/figure/F1/ Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2]<br />{{bull}}[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868890/figure/F2/ Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems]<br />{{bull}}[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3868890/figure/F3/ Figure 3: Schematic of brain pathways involved in food intake]</ref><ref name="OX1-CB1 heterodimer review of function">{{cite journal | vauthors = Thompson MD, Xhaard H, Sakurai T, Rainero I, Kukkonen JP | title = OX1 and OX2 orexin/hypocretin receptor pharmacogenetics | journal = Frontiers in Neuroscience | volume = 8 | page = 57 | year = 2014 | pmid = 24834023 | pmc = 4018553 | doi = 10.3389/fnins.2014.00057 | quote = OX1–CB1 dimerization was suggested to strongly potentiate orexin receptor signaling, but a likely explanation for the signal potentiation is, instead, offered by the ability of OX1 receptor signaling to produce 2-arachidonoyl glycerol, a CB1 receptor ligand, and a subsequent co-signaling of the receptors (Haj-Dahmane and Shen, 2005; Turunen et al., 2012; Jäntti et al., 2013). However, this does not preclude dimerization. | doi-access = free }}</ref><ref name="Human heterodimers: OX1–OX2 OX1–CB1 OX2–CB1">{{cite journal | vauthors = Jäntti MH, Mandrika I, Kukkonen JP | title = Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors | journal = Biochemical and Biophysical Research Communications | volume = 445 | issue = 2 | pages = 486–490 | date = March 2014 | pmid = 24530395 | doi = 10.1016/j.bbrc.2014.02.026 | quote = Orexin receptor subtypes readily formed homo- and hetero(di)mers, as suggested by significant BRET signals. CB1 receptors formed homodimers, and they also heterodimerized with both orexin receptors.&nbsp;... In conclusion, orexin receptors have a significant propensity to make homo- and heterodi-/oligomeric complexes. However, it is unclear whether this affects their signaling. As orexin receptors efficiently signal via endocannabinoid production to CB1 receptors, dimerization could be an effective way of forming signal complexes with optimal cannabinoid concentrations available for cannabinoid receptors. }}</ref> [[adenosine A1 receptor|adenosine A<sub>1</sub> receptors]],<ref name="pmid17093123">{{cite journal | vauthors = Liu ZW, Gao XB | title = Adenosine inhibits activity of hypocretin/orexin neurons by the A1 receptor in the lateral hypothalamus: a possible sleep-promoting effect | journal = Journal of Neurophysiology | volume = 97 | issue = 1 | pages = 837–848 | date = January 2007 | pmid = 17093123 | pmc = 1783688 | doi = 10.1152/jn.00873.2006 }}</ref> [[Muscarinic acetylcholine receptor M3|muscarinic M<sub>3</sub> receptors]],<ref name="pmid18344611">{{cite journal | vauthors = Ohno K, Hondo M, Sakurai T | title = Cholinergic regulation of orexin/hypocretin neurons through M(3) muscarinic receptor in mice | journal = Journal of Pharmacological Sciences | volume = 106 | issue = 3 | pages = 485–491 | date = March 2008 | pmid = 18344611 | doi = 10.1254/jphs.FP0071986 | doi-access = free }}</ref> serotonin [[5-HT1A receptor|5-HT<sub>1A</sub> receptors]],<ref name="pmid15306649">{{cite journal | vauthors = Muraki Y, Yamanaka A, Tsujino N, Kilduff TS, Goto K, Sakurai T | title = Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor | journal = The Journal of Neuroscience | volume = 24 | issue = 32 | pages = 7159–7166 | date = August 2004 | pmid = 15306649 | pmc = 6729168 | doi = 10.1523/JNEUROSCI.1027-04.2004 }}</ref> [[neuropeptide Y]] receptors,<ref name="pmid15470140">{{cite journal | vauthors = Fu LY, Acuna-Goycolea C, van den Pol AN | title = Neuropeptide Y inhibits hypocretin/orexin neurons by multiple presynaptic and postsynaptic mechanisms: tonic depression of the hypothalamic arousal system | journal = The Journal of Neuroscience | volume = 24 | issue = 40 | pages = 8741–8751 | date = October 2004 | pmid = 15470140 | pmc = 6729969 | doi = 10.1523/JNEUROSCI.2268-04.2004 }}</ref> [[cholecystokinin A receptor]]s,<ref name="pmid16093397">{{cite journal | vauthors = Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T | display-authors = 6 | title = Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor | journal = The Journal of Neuroscience | volume = 25 | issue = 32 | pages = 7459–7469 | date = August 2005 | pmid = 16093397 | pmc = 6725310 | doi = 10.1523/JNEUROSCI.1193-05.2005 }}</ref> and [[catecholamines]],<ref name="pmid15634779">{{cite journal | vauthors = Li Y, van den Pol AN | title = Direct and indirect inhibition by catecholamines of hypocretin/orexin neurons | journal = The Journal of Neuroscience | volume = 25 | issue = 1 | pages = 173–183 | date = January 2005 | pmid = 15634779 | pmc = 6725201 | doi = 10.1523/JNEUROSCI.4015-04.2005 }}</ref><ref name="pmid16611835">{{cite journal | vauthors = Yamanaka A, Muraki Y, Ichiki K, Tsujino N, Kilduff TS, Goto K, Sakurai T | title = Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner | journal = Journal of Neurophysiology | volume = 96 | issue = 1 | pages = 284–298 | date = July 2006 | pmid = 16611835 | doi = 10.1152/jn.01361.2005 | citeseerx = 10.1.1.320.260 }}</ref> as well as to [[ghrelin]], [[leptin]], and [[glucose]].<ref name="pmid17910982">{{cite journal | vauthors = Ohno K, Sakurai T | title = Orexin neuronal circuitry: role in the regulation of sleep and wakefulness | journal = Frontiers in Neuroendocrinology | volume = 29 | issue = 1 | pages = 70–87 | date = January 2008 | pmid = 17910982 | doi = 10.1016/j.yfrne.2007.08.001 | s2cid = 7888110 }}</ref> Orexinergic neurons themselves regulate release of [[acetylcholine]],<ref name="pmid14622212">{{cite journal | vauthors = Bernard R, Lydic R, Baghdoyan HA | title = Hypocretin-1 causes G protein activation and increases ACh release in rat pons | journal = The European Journal of Neuroscience | volume = 18 | issue = 7 | pages = 1775–1785 | date = October 2003 | pmid = 14622212 | doi = 10.1046/j.1460-9568.2003.02905.x | hdl-access = free | s2cid = 18515164 | hdl = 2027.42/75751 }}</ref><ref name="pmid17928158">{{cite journal | vauthors = Frederick-Duus D, Guyton MF, Fadel J | title = Food-elicited increases in cortical acetylcholine release require orexin transmission | journal = Neuroscience | volume = 149 | issue = 3 | pages = 499–507 | date = November 2007 | pmid = 17928158 | doi = 10.1016/j.neuroscience.2007.07.061 | s2cid = 19452926 }}</ref> [[serotonin]], and [[noradrenaline]].<ref name="pmid15111023">{{cite journal | vauthors = Soffin EM, Gill CH, Brough SJ, Jerman JC, Davies CH | title = Pharmacological characterisation of the orexin receptor subtype mediating postsynaptic excitation in the rat dorsal raphe nucleus | journal = Neuropharmacology | volume = 46 | issue = 8 | pages = 1168–1176 | date = June 2004 | pmid = 15111023 | doi = 10.1016/j.neuropharm.2004.02.014 | s2cid = 45872346 }}</ref>

Orexinergic neurons can be differentiated into two groups based on connectivity and functionality.  Orexinergic neurons in the [[lateral hypothalamus|lateral hypothalamic]] group are closely associated with reward related functions, such as [[conditioned place preference]]. These neurons preferentially innervate the [[ventral tegmental area]] and the [[ventromedial prefrontal cortex]]. The neurons found in the ventral tegmental area, the ventromedial prefrontal cortex, and the nucleus accumbens shell are strongly implicated in addiction and the sensitization of neurons to stimulating drugs (such as amphetamines). Orexin producing neurons in these areas have been found to be primarily indicated in seeking behavior when externally stimulated by environmental signals such as stress.<ref name = "Mahler_2012">{{Cite book | vauthors = Mahler SV, Smith RJ, Moorman DE, Sartor GC, Aston-Jones G  |title=Orexin/Hypocretin System |date=2012 |chapter=Multiple roles for orexin/hypocretin in addiction |series=Progress in Brain Research |volume=198 |pages=79–121 |doi=10.1016/B978-0-444-59489-1.00007-0 |issn=0079-6123 |pmc=3643893 |pmid=22813971|isbn=978-0-444-59489-1 }}</ref> These neurons are in contrast to the lateral hypothalamic neurons, the perifornical-dorsal group of orexinergic neurons are involved in functions related to arousal and autonomic response.  These neurons project inter-hypothalamically, as well as to the brainstem, where the release of orexin modulates various autonomic processes.<ref>{{cite journal | vauthors = Aston-Jones G, Smith RJ, Sartor GC, Moorman DE, Massi L, Tahsili-Fahadan P, Richardson KA | title = Lateral hypothalamic orexin/hypocretin neurons: A role in reward-seeking and addiction | journal = Brain Research | volume = 1314 | pages = 74–90 | date = February 2010 | pmid = 19815001 | pmc = 2819557 | doi = 10.1016/j.brainres.2009.09.106 }}</ref><ref>{{cite journal | vauthors = Grimaldi D, Silvani A, Benarroch EE, Cortelli P | title = Orexin/hypocretin system and autonomic control: new insights and clinical correlations | journal = Neurology | volume = 82 | issue = 3 | pages = 271–278 | date = January 2014 | pmid = 24363130 | doi = 10.1212/WNL.0000000000000045 | s2cid = 9209963 }}</ref>

== Orexin system dysfunction ==
Orexin/hypocretin system dysfunction might be associated with a variety of disorders and medical conditions.<ref>{{cite journal | vauthors = Al-Kuraishy HM, Abdulhadi MH, Hussien NR, Al-Niemi MS, Rasheed HA, Al-Gareeb AI | title = Involvement of orexinergic system in psychiatric and neurodegenerative disorders: A scoping review | journal = Brain Circulation | volume = 6 | issue = 2 | pages = 70–80 | date = 26 Jun 2020 | pmid = 33033776 | pmc = 7511915 | doi = 10.4103/bc.bc_42_19 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Villano I, La Marra M, Di Maio G, Monda V, Chieffi S, Guatteo E, Messina G, Moscatelli F, Monda M, Messina A | display-authors = 6 | title = Physiological Role of Orexinergic System for Health | journal = International Journal of Environmental Research and Public Health | volume = 19 | issue = 14 | page = 8353 | date = July 2022 | pmid = 35886210 | pmc = 9323672 | doi = 10.3390/ijerph19148353 | doi-access = free }}</ref>
   
=== Takotsubo syndrome ===
Orexin/hypocretin system dysfunction has been proposed as a novel pathophysiological model of [[Takotsubo cardiomyopathy|Takotsubo syndrome]] (acute failure syndrome).<ref>{{cite journal | vauthors = Knez R, Niksic M, Omerovic E | title = Orexin/hypocretin system dysfunction in patients with Takotsubo syndrome: A novel pathophysiological explanation | journal = Frontiers in Cardiovascular Medicine | volume = 9 | article-number = 1016369 | date = 3 Nov 2022 | pmid = 36407467 | pmc = 9670121 | doi = 10.3389/fcvm.2022.1016369 | doi-access = free }}</ref>

=== ESSENCE ===
ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) is an umbrella term covering a wide range of neurodevelopmental disorders and difficulties (ADHD, developmental coordination disorder, autism spectrum disorder) as well as ESSENCE-associated conditions (behavioural phenotype syndromes, some neurological conditions and disorders, and severe early-onset mental disorders). Orexin/hypocretin system dysfunction might be associated with many symptoms in a variety of ESSENCE.<ref>{{cite journal | vauthors = Knez R, Stevanovic D, Fernell E, Gillberg C | title = Orexin/Hypocretin System Dysfunction in ESSENCE (Early Symptomatic Syndromes Eliciting Neurodevelopmental Clinical Examinations) | journal = Neuropsychiatric Disease and Treatment | volume = 18 | pages = 2683–2702 | date = 15 Nov 2022 | pmid = 36411777 | pmc = 9675327 | doi = 10.2147/NDT.S358373 | doi-access = free }}</ref>

== Clinical uses ==

The orexin/hypocretin system is the target of the insomnia medication [[suvorexant]] (Belsomra), which works by blocking both orexin receptors.<ref>{{cite web|url=http://www.belsomra.com/|title=BELSOMRA® (suvorexant) C-IV |work=Belsomra |access-date=2015-10-31}}</ref> Suvorexant has undergone three phase III trials and was approved in 2014 by the [[US Food and Drug Administration]] (FDA) after being denied approval the year before.<ref>{{cite web|url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm|archive-url=https://web.archive.org/web/20140814055202/http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm|archive-date=August 14, 2014|title=FDA approves new type of sleep drug, Belsomra|work=Food and Drug Administration (FDA)|date=2014-08-31| veditors = Ventura J |access-date=2015-10-31}}</ref> The other FDA-approved [[Orexin antagonist|orexin antagonists]] are [[lemborexant]] (Dayvigo)<ref name="Dayvigo FDA label">{{cite web | title=Dayvigo- lemborexant tablet, film coated | work = DailyMed | publisher = U.S. National Library of Medicine | url= https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7074cb65-77b3-45d2-8e8d-da8dc0f70bfd | access-date=30 September 2021}}</ref> and [[daridorexant]] (Quviviq).<ref name="Quviviq FDA label">{{cite web | title="Quviviq- daridorexant tablet | website=fda.gov | url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf| archive-url=https://web.archive.org/web/20220111235156/https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/214985s000lbl.pdf| archive-date=January 11, 2022}}</ref>

In 2016, the [[University of Texas Health Science Center]] registered a clinical trial for the use of suvorexant for people with [[cocaine dependence]]. They plan to measure cue reactivity, anxiety and stress.<ref>{{ClinicalTrialsGov|NCT02785406|Role of the Orexin Receptor System in Stress, Sleep and Cocaine Use}}</ref>

In 2022, the [[European Medicines Agency]] authorized the use of [[daridorexant]] (Quviviq) for sleep initiation and maintenance disorders.<ref name="Quviviq EMA authorization">{{cite web | title=Quviviq | website=European Medicines Agency | date=22 February 2022 | url= https://www.ema.europa.eu/en/medicines/human/EPAR/quviviq}}</ref>

=== Other potential uses ===

[[Route of administration#Inhalation|Intranasal]] orexin is able to increase cognition in primates, especially under sleep deprived situations,<ref>{{cite journal | vauthors = Nixon JP, Mavanji V, Butterick TA, Billington CJ, Kotz CM, Teske JA | title = Sleep disorders, obesity, and aging: the role of orexin | journal = Ageing Research Reviews | volume = 20 | pages = 63–73 | date = March 2015 | pmid = 25462194 | pmc = 4467809 | doi = 10.1016/j.arr.2014.11.001 }}</ref> which may provide an opportunity for the treatment of excessive daytime sleepiness.<ref>{{cite journal | vauthors = Billiard M | title = Narcolepsy: current treatment options and future approaches | journal = Neuropsychiatric Disease and Treatment | volume = 4 | issue = 3 | pages = 557–566 | date = June 2008 | pmid = 18830438 | pmc = 2526380 }}</ref>

A study has reported that transplantation of orexin neurons into the pontine [[reticular formation]] in rats is feasible, indicating the development of alternative therapeutic strategies in addition to pharmacological interventions to treat narcolepsy.<ref name="pmid15683135">{{cite journal | vauthors = Arias-Carrión O, Murillo-Rodriguez E, Xu M, Blanco-Centurion C, Drucker-Colín R, Shiromani PJ | title = Transplantation of hypocretin neurons into the pontine reticular formation: preliminary results | journal = Sleep | volume = 27 | issue = 8 | pages = 1465–1470 | date = December 2004 | pmid = 15683135 | pmc = 1201562 | doi = 10.1093/sleep/27.8.1465 | url = http://www.journalsleep.org/Articles/270802.pdf | archive-url = https://web.archive.org/web/20160303180701/http://www.journalsleep.org/Articles/270802.pdf | archive-date = 2016-03-03 }}</ref>

Orexins are also thought to have potential implications in learning and aiding in fending off diseases such as dementia and other disorders that impair cognition.<ref name = "Mahler_2012" />

== Evolution ==
{{Infobox protein family
| Symbol = Orexin
| Name = Prepro-orexin
| width =
| caption = 
| Pfam = PF02072
| InterPro = IPR001704
| SMART=
| Prosite =
| SCOP = 1cq0
| TCDB =
| OPM protein = 1wso
| PDB=
}}
The exon architecture of orexin is conserved in all [[vertebrate]]s.<ref>{{cite journal | vauthors = López JM, Sanz-Morello B, González A | title = Organization of the orexin/hypocretin system in the brain of two basal actinopterygian fishes, the cladistians Polypterus senegalus and Erpetoichthys calabaricus | journal = Peptides | volume = 61 | pages = 23–37 | date = November 2014 | pmid = 25169954 | doi = 10.1016/j.peptides.2014.08.011 | s2cid = 34333729 }}</ref> 
{{-}}

== References ==
{{Reflist|30em}}

== External links ==
{{Commonscat}}
* {{MeshName|orexins}}
* [https://sleepfoundation.org/sleep-news/compare-different-sleep-aids Compare Different Sleep Aids], ''National Sleep Foundation''
* [https://sleepfoundation.org/sleep-news/orexin-receptor-antagonists-new-class-sleeping-pill Orexin receptor antagonists: A new class of sleeping pill], ''National Sleep Foundation''

{{Orexigenics}}
{{Neuropeptides}}
{{Orexin receptor modulators}}

[[Category:Molecular neuroscience]]
[[Category:Neuropeptides]]
[[Category:Orexin receptor agonists]]
[[Category:Wakefulness-promoting agents]]