View source for Orexin

{{Primary sources|date=March 2012}}
{{Pfam box
| Symbol = Orexin
| Name = Prepro-orexin
| image = 1R02 crystallography.png
| width =
| caption = Solution phase [[NMR]] structure of orexin A based on the [[Protein Data Bank|PDB]] coordinates {{PDB2|1R02}}.
| Pfam = PF02072
| InterPro = IPR001704
| SMART=
| Prosite =
| SCOP = 1cq0
| TCDB =
| OPM family =145
| OPM protein = 1wso
| PDB= 
}}
{{Infobox protein
|Name=orexin (hypocretin) neuropeptide precursor
|caption=Solution phase NMR structure of orexin B based on the [[Protein Data Bank|PDB]] coordinates {{PDB2|1CQ0}}.
|image=1CQ0 crystallography.png
|width=
|HGNCid=4847
|Symbol=HCRT
|AltSymbols=PPOX, OX
|EntrezGene=3060
|OMIM=602358
|RefSeq=NM_001524
|UniProt=O43612
|PDB=
|ECnumber=
|Chromosome=17
|Arm=q
|Band=21
|LocusSupplementaryData=
}}

'''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 |  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 = 9780387922713 }}</ref> The most common form of [[narcolepsy]], in which the sufferer experiences brief losses of muscle tone ([[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 = 161–8 | date = October 2000 | pmid = 11020209 | doi = 10.1002/1097-4547(20001015)62:2<161::AID-JNR1>3.0.CO;2-1 }}</ref>

There are only 10,000–20,000&nbsp;orexin-producing [[neurons]] in the human brain,<ref name="Stanford"/> 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 | url = https://books.google.com/books?id=OHIu9l7bAmsC&lpg=PA195 | page = 195 | title =  The Orexin/Hypocretin System: Physiology and Pathophysiology |veditors=Nishino S, Sakurai T | publisher = Springer | year = 2006 | isbn = 9781592599509 }}</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 | 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 = 573–85 | date = February 1998 | pmid = 9491897 | doi = 10.1016/S0092-8674(00)80949-6 }}</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 | 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 = 322–7 | date = January 1998 | pmid = 9419374 | pmc = 18213 | doi = 10.1073/pnas.95.1.322 }}</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/> The use of both terms is now a practical necessity, as ''hypocretin'' is used to refer to the genetic products and ''orexin'' is used to refer to the protein products.<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 }}</ref> There is a high affinity 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 = 2875–87 | 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 OX<sub>1</sub>R and OX<sub>2</sub>R.<ref name="pmid9491897"/>

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 | 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 = 8733–8 | date = August 1996 | pmid = 8710940 | pmc = 38742 | doi = 10.1073/pnas.93.16.8733 }}</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 = 227–30 | date = May 2002 | pmid = 11983761 | pmc = 1279673 }}</ref> These cells were first thought to reside and work only within the lateral hypothalamus area, but immunocytochemistry tactics 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. 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 -B (hypocretin-1 and -2). They are excitatory [[neuropeptide]]s with approximately 50% sequence identity, produced by cleavage of a single precursor protein. 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. 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 = 340–6 | date = January 2004 | pmid = 14691055 | pmc = 1574197 | doi = 10.1038/sj.bjp.0705610 }}</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 = 124–30 | 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.

=== Brown fat activation ===
Obesity in orexin [[knockout mice]] is a result of inability of brown preadipocytes to differentiate into [[brown adipose tissue]] (BAT), which in turn reduces BAT [[thermogenesis]]. BAT differentiation can be restored in these knockout mice through injections of orexin. Deficiency in orexin has also been linked to [[narcolepsy]], a sleep disorder. Furthermore, narcoleptic people are more likely to be obese.  Hence obesity in narcoleptic patients may be due to orexin deficiency leading to impaired thermogenesis and energy expenditure.<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 = 478–90 | date = October 2011 | pmid = 21982708 | doi = 10.1016/j.cmet.2011.08.010 | laysummary = https://www.sciencedaily.com/releases/2011/10/111004123554.htm | laysource = ScienceDaily }}</ref>

=== Wakefulness ===
Orexin seems to promote wakefulness. Recent 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 = 4705–21 | date = June 1998 | pmid = 9614245 | doi =  | url = http://www.jneurosci.org/cgi/content/full/18/12/4705 }}</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 = 4568–76 | date = June 2002 | pmid = 12040064 | doi = <!-- 20026455 --> | url = http://www.jneurosci.org/content/22/11/4568.full}}</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 | 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 = 365–76 | date = August 1999 | pmid = 10458611 | doi = 10.1016/S0092-8674(00)81965-0 }}</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 | title = Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation | journal = Cell | volume = 98 | issue = 4 | pages = 437–51 | date = August 1999 | pmid = 10481909 | doi = 10.1016/S0092-8674(00)81973-X }}</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 = 6291–300 | date = July 2004 | pmid = 15254084 | 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.

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 food intake. In fact, orexin-deficient narcoleptic patients 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 web | url = https://www.wired.com/science/discoveries/news/2007/12/sleep_deprivation | title = Snorting a Brain Chemical Could Replace Sleep |accessdate = 2008-02-05 | author= [[Alexis Madrigal]] | date= 2007-12-28 | 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 = 14239–47 | date = December 2007 | pmid = 18160631 | 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 = 782–6 | date = September 2000 | pmid = 10984567 | doi = 10.1056/NEJM200009143431106 }}</ref> Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans 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, Hong SS, 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 | title = Narcolepsy is strongly associated with the T-cell receptor alpha locus | journal = Nature Genetics | volume = 41 | issue = 6 | pages = 708–11 | 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 narcoleptic humans 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| format = | work = EurekAlert | publisher = American Association for the Advancement of Science | pages = | quote = | accessdate = 2009-05-31}}</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 = 1202–16 | date = March 2009 | pmid = 19008313 | pmc = 2654731 | doi = 10.1210/en.2008-0293 | url = http://press.endocrine.org/doi/10.1210/en.2008-0293?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%3dpubmed }}</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 = 526–9 | date = March 1999 | pmid = 10064841 | doi = 10.1016/S0006-8993(99)01131-2 | url = http://www.sciencedirect.com/science/article/pii/S0006899399011312 }}</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 = 335–48 | date = March 2010 | pmid = 19489767 | doi = 10.1111/j.1748-1716.2009.02008.x }}</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 recently 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 | title = Promotion of sleep by targeting the orexin system in rats, dogs and humans | journal = Nature Medicine | volume = 13 | issue = 2 | pages = 150–5 | date = February 2007 | pmid = 17259994 | doi = 10.1038/nm1544 }}</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 = 171–81 | date = March 2007 | pmid = 17299454 | doi = 10.1038/nrn2092 }}</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 | pages = 18 | date = 2013-03-06 | pmid = 23508038 | pmc = 3589707 | doi = 10.3389/fendo.2013.00018 }}</ref>

=== Addiction ===
Preliminary research has been conducted that 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 = 556–9 | date = September 2005 | pmid = 16100511 | doi = 10.1038/nature04071 }}</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 rat]]s 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]] }}</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 = 752–9 | date = July 2006 | pmid = 16751790 | pmc = 1617074 | doi = 10.1038/sj.bjp.0706789 }}</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 suffered 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 | work = | 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 | pages = e0173967 | date = 2017 | pmid = 28296947 | pmc = 5351999 | doi = 10.1371/journal.pone.0173967 }}</ref>

=== Lipid metabolism ===
Orexin-A (OXA) has been recently 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 | 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 = 1841–52 | date = July 2011 | pmid = 21505958 | doi = 10.1007/s00125-011-2152-2 }}</ref> The link between OXA and the lipid metabolism is new and currently under more research.

Obesity in orexin-[[knockout mice]] is associated with impaired [[brown adipose tissue]] thermogenesis.<ref name="pmid21982708" />

=== 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 | title = Human hypocretin and melanin-concentrating hormone levels are linked to emotion and social interaction | journal = Nature Communications | volume = 4 | pages = 1547 | year = 2013 | pmid = 23462990 | pmc = 3595130 | doi = 10.1038/ncomms2461 | laysummary = https://www.sciencedaily.com/releases/2013/03/130307145720.htm | laysource = 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.

== 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 = 3013–22 | date = March 2004 | pmid = 15044540 | doi = 10.1523/JNEUROSCI.5416-03.2004 }}</ref> [[cannabinoid receptor 1]] and {{abbr|CB1–OX1|cannabinoid-1 and orexin-1}} [[GPCR oligomer|receptor heterodimer]]s,<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 | issue =  | pages = 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. }}<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 | issue =  | pages = 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. }}</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 = 486–90 | 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 = 837–48 | 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 = 485–91 | date = March 2008 | pmid = 18344611 | doi = 10.1254/jphs.FP0071986 | url = http://joi.jlc.jst.go.jp/JST.JSTAGE/jphs/FP0071986?from=PubMed | dead-url = yes | archive-url = https://archive.is/20121219051258/http://joi.jlc.jst.go.jp/JST.JSTAGE/jphs/FP0071986?from=PubMed | archive-date = 2012-12-19 }}</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 = 7159–66 | date = August 2004 | pmid = 15306649 | 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 = 8741–51 | date = October 2004 | pmid = 15470140 | 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 | title = Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor | journal = The Journal of Neuroscience | volume = 25 | issue = 32 | pages = 7459–69 | date = August 2005 | pmid = 16093397 | 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 = 173–83 | date = January 2005 | pmid = 15634779 | 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 = 284–98 | date = July 2006 | pmid = 16611835 | doi = 10.1152/jn.01361.2005 }}</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 }}</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 = 1775–85 | date = October 2003 | pmid = 14622212 | doi = 10.1046/j.1460-9568.2003.02905.x }}</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 }}</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 = 1168–76 | date = June 2004 | pmid = 15111023 | doi = 10.1016/j.neuropharm.2004.02.014 }}</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]].  In contrast to the lateral hypothalamic neurons, the perifornical-dorsal group of orexinergic neurons 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 = 271–8 | date = January 2014 | pmid = 24363130 | doi = 10.1212/WNL.0000000000000045 }}</ref>

== Clinical uses ==

The orexin/hypocretin system is the target of the insomnia medication [[suvorexant]], which works by blocking both orexin receptors. 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=http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm|title=FDA approves new type of sleep drug, Belsomra|work=Food and Drug Administration (FDA)|date=2014-08-31|editor-last=Ventura|editor-first=Jeff|accessdate=2015-10-31}}</ref> It is [[trade name|marketed]] as ''[[Belsomra]]''.<ref>{{cite web|url=http://www.belsomra.com/|title=BELSOMRA® (suvorexant) C-IV |work=Belsomra |accessdate=2015-10-31}}</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>{{cite web|url=https://clinicaltrials.gov/ct2/show/NCT02785406|title=Role of the Orexin Receptor System in Stress, Sleep and Cocaine Use (NCT02785406) |work=ClinicalTrials.gov |accessdate=2017-07-08}}</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 = 557–66 | 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 = 1465–70 | date = December 2004 | pmid = 15683135 | pmc = 1201562 | doi =  | url = http://www.journalsleep.org/Articles/270802.pdf | deadurl = yes | archiveurl = https://web.archive.org/web/20160303180701/http://www.journalsleep.org/Articles/270802.pdf | archivedate = 2016-03-03 | df =  }}</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}}
{{Neuropeptidergics}}

[[Category:Neuropeptides]]
[[Category:Molecular neuroscience]]