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[[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.
[[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.{{citation needed|date=September 2011}} 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>http://journal.frontiersin.org/Journal/10.3389/fendo.2013.00018/full</ref>
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.{{citation needed|date=September 2011}} 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|last1=Inutsuka|first1=Ayumu|last2=Yamanaka|first2=Akihiro|title=The physiological role of orexin/hypocretin neurons in the regulation of sleep/wakefulness and neuroendocrine functions|journal=Frontiers in Endocrinology|date=2013-03-06|volume=4|issue=18|doi=10.3389/fendo.2013.00018|url=http://journal.frontiersin.org/article/10.3389/fendo.2013.00018/full|accessdate=2015-10-31|issn=1664-2392}}</ref>


=== Pharmacologic potential ===
=== Pharmacologic potential ===
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Orexins and [[orexin receptor]] agonists can increase alertness like [[substituted amphetamine]]s, but with fewer side effects.
Orexins and [[orexin receptor]] agonists can increase alertness like [[substituted amphetamine]]s, but with fewer side effects.


Merck reported at the Sleep 2012 conference that insomniacs taking an orexin blocker, [[suvorexant]], fell asleep faster and slept an hour longer. Suvorexant was tested for three months on over a thousand patients in a phase III trial. Survorexant has undergone three phase III trials and was approved on August 13, 2014 by the US Food and Drug Administration (FDA) after being denied approval the year before.<ref>http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm409950.htm</ref> It is available as "[[Belsomra]]".<ref>http://www.belsomra.com/</ref>
Merck reported at the Sleep 2012 conference that insomniacs taking an orexin blocker, [[suvorexant]], fell asleep faster and slept an hour longer. Suvorexant was tested for three months on over a thousand patients in a phase III trial. Survorexant has undergone three phase III trials and was approved on August 13, 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=20114-08-31|editor-last=Ventura|editor-first=Jeff|accessdate=2015-10-31}}</ref> It is available as "[[Belsomra]]".<ref>{{cite web|url=http://www.belsomra.com/|title=BELSOMRA® (suvorexant) C-IV |work=Belsomra |accessdate=2015-10-31}}</ref>


Preliminary research has been conducted that shows potential for orexin blockers in the treatment of [[alcoholism]]. [[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 | author = Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B | title = The orexin system regulates alcohol-seeking in rats | journal = Br. J. Pharmacol. | volume = 148 | issue = 6 | pages = 752–9 | year = 2006 | pmid = 16751790 | doi = 10.1038/sj.bjp.0706789 | pmc = 1617074 }}</ref>
Preliminary research has been conducted that shows potential for orexin blockers in the treatment of [[alcoholism]]. [[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 | author = Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B | title = The orexin system regulates alcohol-seeking in rats | journal = Br. J. Pharmacol. | volume = 148 | issue = 6 | pages = 752–9 | year = 2006 | pmid = 16751790 | doi = 10.1038/sj.bjp.0706789 | pmc = 1617074 }}</ref>
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[[Masashi Yanagisawa]] and colleagues at the [[University of Texas Southwestern Medical Center at Dallas]], coined the term ''orexin'' to reflect the orexigenic (appetite-stimulating) activity of these peptides. In their 1998 paper (with authorship attributed to Sakurai and colleagues) 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"/>
[[Masashi Yanagisawa]] and colleagues at the [[University of Texas Southwestern Medical Center at Dallas]], coined the term ''orexin'' to reflect the orexigenic (appetite-stimulating) activity of these peptides. In their 1998 paper (with authorship attributed to Sakurai and colleagues) 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"/>


In 1998, Luis de Lecea, [[Thomas Kilduff]], and colleagues also reported discovery of these same peptides, dubbing them ''hypocretins'' to indicate that they are synthesized in the [[hypothalamus]] and to reflect their structural similarity to the hormone [[secretin]] (i.e., ''hypo''thalamic se''cretin''). This is the same group that first identified clone 35 two years earlier.<ref name="pmid9419374"/><ref name="pmid8710940"/> De Lecea and colleagues were originally in search of novel genes expressed in the hypothalamus. To do this, they extracted selective DNA found in the lateral hypothalamus. They cloned this DNA and studied it under electron microscopy. Neurotransmitters found in this area were oddly similar to the gut hormone, secretin, so de Lecea decided to name the two forms of peptides hypocretin-1 and hypocretin-2.<ref>http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1279673/</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).
In 1998, Luis de Lecea, [[Thomas Kilduff]], and colleagues also reported discovery of these same peptides, dubbing them ''hypocretins'' to indicate that they are synthesized in the [[hypothalamus]] and to reflect their structural similarity to the hormone [[secretin]] (i.e., ''hypo''thalamic se''cretin''). This is the same group that first identified clone 35 two years earlier.<ref name="pmid9419374"/><ref name="pmid8710940"/> De Lecea and colleagues were originally in search of novel genes expressed in the hypothalamus. To do this, they extracted selective DNA found in the lateral hypothalamus. They cloned this DNA and studied it under electron microscopy. Neurotransmitters found in this area were oddly similar to the gut hormone, secretin, so de Lecea decided to name the two forms of peptides hypocretin-1 and hypocretin-2.<ref>{{cite journal|last1=Ebrahim|first1=IO|last2=Howard|first2=RS|last3=Kopelman|first3=MD|last4=Sharief|first4=MK|last5=Williams|first5=AJ|title=The hypocretin/orexin system.|journal=Journal of the Royal Society of Medicine|date=May 2002|volume=95|issue=5|pages=227-30|pmid=11983761|pmc=1279673|url=http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1279673/|accessdate=2015-10-31}}</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).


The name of this family of peptides is currently an unsettled issue. The name "orexin" has been rejected by some due to evidence that the orexigenic effects of these peptides may be incidental or trivial (i.e., orexin induced subjects eat more because they are awake more), though this issue is also unsettled, while other groups maintain that the name "hypocretin" is awkward, pointing out that many neuropeptides have names that are unrelated to their most important functions, and that waking is one of the important factors that supports feeding behavior. A compromise position regards both "hypocretin" and "orexin" as acceptable terms with "hypocretin" referring to the gene and "orexin" referring to the protein products. This is reflected by the use of "HCRT" as the standard gene symbol in databases like [[GenBank]] and "OX" by the [[International Union of Basic and Clinical Pharmacology]].<ref name="pmid22759794">{{cite journal | doi = 10.1124/pr.111.005546 |vauthors=Gotter AL, Webber AL, etal | 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 | year = 2012 | pmid = 22759794 }}</ref>
The name of this family of peptides is currently an unsettled issue. The name "orexin" has been rejected by some due to evidence that the orexigenic effects of these peptides may be incidental or trivial (i.e., orexin induced subjects eat more because they are awake more), though this issue is also unsettled, while other groups maintain that the name "hypocretin" is awkward, pointing out that many neuropeptides have names that are unrelated to their most important functions, and that waking is one of the important factors that supports feeding behavior. A compromise position regards both "hypocretin" and "orexin" as acceptable terms with "hypocretin" referring to the gene and "orexin" referring to the protein products. This is reflected by the use of "HCRT" as the standard gene symbol in databases like [[GenBank]] and "OX" by the [[International Union of Basic and Clinical Pharmacology]].<ref name="pmid22759794">{{cite journal | doi = 10.1124/pr.111.005546 |vauthors=Gotter AL, Webber AL, etal | 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 | year = 2012 | pmid = 22759794 }}</ref>
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==References==
==References==
{{Reflist|2}}
{{Reflist|30em}}


==External links==
==External links==
* {{MeshName|orexins}}
* {{MeshName|orexins}}
*http://www.sleepfoundation.org/article/compare-different-sleep-aids
* [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''
*http://www.sleepfoundation.org/alert/drug-may-offer-new-approach-treating-insomnia
⚫
*http://www.sleepfoundation.org/article/orexin-receptor-antagonists-new-class-sleeping-pill


{{Neuropeptides}}
{{Neuropeptides}}

Revision as of 20:02, 31 October 2015

Prepro-orexin
Solution phase NMR structure of orexin A based on the PDB coordinates 1R02​.
Identifiers
SymbolOrexin
PfamPF02072
InterProIPR001704
SCOP21cq0 / SCOPe / SUPFAM
OPM superfamily154
OPM protein1wso
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary
PDB1cq0A:71-97 1wsoA:35-66 1r02A:34-66 1uvqC:1-13
orexin (hypocretin) neuropeptide precursor
Solution phase NMR structure of orexin B based on the PDB coordinates 1CQ0​.
Identifiers
SymbolHCRT
Alt. symbolsPPOX, OX
NCBI gene3060
HGNC4847
OMIM602358
RefSeqNM_001524
UniProtO43612
Other data
LocusChr. 17 q21
Search for
StructuresSwiss-model
DomainsInterPro

Orexin, also called hypocretin, is a neuropeptide that regulates arousal, wakefulness, and appetite.[1] The most common form of narcolepsy, in which the sufferer briefly loses muscle tone (cataplexy), is caused by a lack of orexin in the brain due to destruction of the cells that produce it.[2]

The brain contains very few cells that produce orexin; there are about 10,000–20,000 orexin neurons in the human brain, which project out of the nucleus in the lateral hypothalamus.[1][2] However, the axons from these neurons extend throughout the entire brain and spinal cord,[3] where there are also receptors for orexin.

Orexin was discovered in 1998 almost simultaneously by two independent groups of rat-brain researchers.[4][5] One group named it orexin, from orexis, meaning "appetite" in Greek; the other group named it hypocretin, because it is produced in the hypothalamus and bears a weak resemblance to secretin, another peptide.[2] The scientific community has not yet settled on a consensus for which word to use.

Isoforms

There are two types of orexin: orexin-A and -B (hypocretin-1 and -2). They are excitatory neuropeptides 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 bonds; orexin-B is a linear 28 amino acid residue peptide. Studies suggest that orexin-A may be of greater biological importance than orexin-B.[citation needed] 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 orexin receptors, OX1 and OX2, with orexin-A binding to both OX1 and OX2 with approximately equal affinity while orexin-B binds mainly to OX2 and is 5 times less potent as OX1.[6]

The orexins are strongly conserved peptides, found in all major classes of vertebrates.[citation needed]

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 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.[7]

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[8][9] 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[10] in Doberman Pinschers 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.[11] 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.[12] 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 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 hours and then injecting them with the neurochemical alleviates the cognitive deficiencies normally seen with such amount of sleep loss.[13][14]

In humans, narcolepsy is associated with a specific variant of the human leukocyte antigen (HLA) complex.[15] Furthermore, genome-wide analysis shows that, in addition to the HLA variant, narcoleptic humans also exhibit a specific genetic mutation in the T-cell receptor alpha locus.[16] In conjunction, these genetic anomalies cause the immune system to attack and kill the critical orexin neurons. Hence the absence of orexin-producing neurons in narcoleptic humans may be the result of an autoimmune disorder.[17]

Food intake

Orexin increases the craving for food, and correlates with the function of the substances that promote its production.

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.[citation needed] 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.[18]

Pharmacologic potential

Orexins and orexin receptor agonists can increase alertness like substituted amphetamines, but with fewer side effects.

Merck reported at the Sleep 2012 conference that insomniacs taking an orexin blocker, suvorexant, fell asleep faster and slept an hour longer. Suvorexant was tested for three months on over a thousand patients in a phase III trial. Survorexant has undergone three phase III trials and was approved on August 13, 2014 by the US Food and Drug Administration (FDA) after being denied approval the year before.[19] It is available as "Belsomra".[20]

Preliminary research has been conducted that shows potential for orexin blockers in the treatment of alcoholism. Lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.[21][22]

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.[23]

Because orexin-A receptors have been shown to regulate relapse to cocaine seeking, a new study investigated its relation to nicotine by studying rats. By blocking the orexin-A receptor with low doses of the selective antagonist SB-334,867, nicotine self-administration decreased and also the motivation to seek and obtain the drug. The study showed that blocking of receptors in the insula decreased self-administration, but not blocking of receptors in the adjacent somatosensory cortex. The greatest decrease in self-administration was found when blocking all orexin-A receptors in the brain as a whole. A rationale for this study was the fact that the insula has been implicated in regulating feelings of craving. The insula contains orexin-A receptors. It has been reported that smokers who sustained damage to the insula lost the desire to smoke.[24]

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.[25] 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.[7]

Mood

High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.[26] The finding suggests that boosting levels of orexin-A could elevate mood in humans, being thus a possible future treatment for disorders like depression. Likewise, it helps explain the incidence of depression associated with narcolepsy.

History and nomenclature

In 1996, Gautvik, de Lecea, and colleagues 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.[27]

Masashi Yanagisawa and colleagues at the University of Texas Southwestern Medical Center at Dallas, coined the term orexin to reflect the orexigenic (appetite-stimulating) activity of these peptides. In their 1998 paper (with authorship attributed to Sakurai and colleagues) describing these neuropeptides, they also reported discovery of two orexin receptors, dubbed OX1R and OX2R.[4]

In 1998, Luis de Lecea, Thomas Kilduff, and colleagues also reported discovery of these same peptides, dubbing them hypocretins to indicate that they are synthesized in the hypothalamus and to reflect their structural similarity to the hormone secretin (i.e., hypothalamic secretin). This is the same group that first identified clone 35 two years earlier.[5][27] De Lecea and colleagues were originally in search of novel genes expressed in the hypothalamus. To do this, they extracted selective DNA found in the lateral hypothalamus. They cloned this DNA and studied it under electron microscopy. Neurotransmitters found in this area were oddly similar to the gut hormone, secretin, so de Lecea decided to name the two forms of peptides hypocretin-1 and hypocretin-2.[28] 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).

The name of this family of peptides is currently an unsettled issue. The name "orexin" has been rejected by some due to evidence that the orexigenic effects of these peptides may be incidental or trivial (i.e., orexin induced subjects eat more because they are awake more), though this issue is also unsettled, while other groups maintain that the name "hypocretin" is awkward, pointing out that many neuropeptides have names that are unrelated to their most important functions, and that waking is one of the important factors that supports feeding behavior. A compromise position regards both "hypocretin" and "orexin" as acceptable terms with "hypocretin" referring to the gene and "orexin" referring to the protein products. This is reflected by the use of "HCRT" as the standard gene symbol in databases like GenBank and "OX" by the International Union of Basic and Clinical Pharmacology.[29]

Orexin neuron neurotransmitters

Orexinergic neurons have been shown to be sensitive to inputs from Group III metabotropic glutamate receptors,[30] cannabinoid receptor 1 and CB1–OX1 receptor heterodimers,[31][32][33] adenosine A1 receptors,[34] muscarinic M3 receptors,[35] serotonin 5-HT1A receptors,[36] neuropeptide Y receptors,[37] cholecystokinin A receptors,[38] and catecholamines,[39][40] as well as to ghrelin, leptin, and glucose.[41] Orexinergic neurons themselves regulate release of acetylcholine,[42][43] serotonin and noradrenaline.[44]

See also

References

  1. ^ a b Davis JF, Choi DL, Benoit SC (2011). "24. Orexigenic Hypothalamic Peptides Behavior and Feeding - 24.5 Orexin". In Preedy VR, Watson RR, Martin CR (ed.). Handbook of Behavior, Food and Nutrition. Springer. pp. 361–2. ISBN 9780387922713.{{cite book}}: CS1 maint: multiple names: authors list (link)
  2. ^ a b c Stanford Center for Narcolepsy FAQ (retrieved 27-Mar-2012)
  3. ^ Marcus JN, Elmquist JK (2006). "3. Orexin Projections and Localization of Orexin Receptors". In Nishino S, Sakurai T (ed.). The Orexin/Hypocretin System: Physiology and Pathophysiology. Springer. p. 195. ISBN 9781592599509.
  4. ^ a b 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 (1998). "Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior". Cell. 92 (4): 573–85. doi:10.1016/S0092-8674(00)80949-6. PMID 9491897.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b 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 (1998). "The hypocretins: Hypothalamus-specific peptides with neuroexcitatory activity". Proc. Natl. Acad. Sci. U.S.A. 95 (1): 322–7. doi:10.1073/pnas.95.1.322. PMC 18213. PMID 9419374.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Langmead CJ, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ (January 2004). "Characterisation of the binding of 3H-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor". Br. J. Pharmacol. 141 (2): 340–6. doi:10.1038/sj.bjp.0705610. PMC 1574197. PMID 14691055.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ a b Sellayah D, Bharaj P, Sikder D (October 2011). "Orexin is required for brown adipose tissue development, differentiation, and function". Cell Metab. 14 (4): 478–90. doi:10.1016/j.cmet.2011.08.010. PMID 21982708. {{cite journal}}: Unknown parameter |laysource= ignored (help); Unknown parameter |laysummary= ignored (help)CS1 maint: multiple names: authors list (link)
  8. ^ Sherin JE, Elmquist JK, Torrealba F, Saper CB (June 1998). "Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat". The Journal of Neuroscience. 18 (12): 4705–21. PMID 9614245.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Lu J, Bjorkum AA, Xu M, Gaus SE, Shiromani PJ, Saper CB (June 2002). "Selective activation of the extended ventrolateral preoptic nucleus during rapid eye movement sleep". J. Neurosci. 22 (11): 4568–76. PMID 12040064.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ Lin L, Faraco J, et al. (1999). "The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene". Cell. 98 (3): 365–376. doi:10.1016/S0092-8674(00)81965-0. PMID 10458611.
  11. ^ Chemelli RM, Willie JT, et al. (1999). "Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation". Cell. 98 (4): 437–451. doi:10.1016/S0092-8674(00)81973-X. PMID 10481909.
  12. ^ Mochizuki T, Crocker A, McCormack S, Yanagisawa M, Sakurai T, Scammell TE (July 2004). "Behavioral state instability in orexin knock-out mice". J. Neurosci. 24 (28): 6291–300. doi:10.1523/JNEUROSCI.0586-04.2004. PMID 15254084.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Alexis Madrigal (2007-12-28). "Snorting a Brain Chemical Could Replace Sleep". Wired News, Condé Nast. Retrieved 2008-02-05.
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     • Figure 1: Schematic of brain CB1 expression and orexinergic neurons expressing OX1 or OX2
     • Figure 2: Synaptic signaling mechanisms in cannabinoid and orexin systems
     • Figure 3: Schematic of brain pathways involved in food intake
  32. ^ Thompson MD, Xhaard H, Sakurai T, Rainero I, Kukkonen JP (2014). "OX1 and OX2 orexin/hypocretin receptor pharmacogenetics". Front Neurosci. 8: 57. doi:10.3389/fnins.2014.00057. PMC 4018553. PMID 24834023. 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.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  33. ^ Jäntti MH, Mandrika I, Kukkonen JP (2014). "Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors". Biochem. Biophys. Res. Commun. 445 (2): 486–90. doi:10.1016/j.bbrc.2014.02.026. PMID 24530395. 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. ... 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.
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