Orexin
Orexin (
There are 50,000–80,000 orexin-producing
Orexin was discovered in 1998 almost simultaneously by two independent groups of researchers working on the
Discovery
In 1998, reports of the discovery of orexin/hypocretin were published nearly simultaneously. Luis de Lecea,
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
On the other hand, Sakurai and colleagues were studying the orexin system as orphan receptors. 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'.[11]
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.[13] 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.[14]
Isoforms
There are two types of orexin:
The orexins are strongly conserved peptides, found in all major classes of vertebrates.[22]
Function
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. The orexin system has been hypothesized 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.[23]
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.[24][25] Although orexin
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[28][29] and appear to play an important role in stabilizing wakefulness and sleep.
The discovery that an orexin receptor mutation causes the
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 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.[34][35]
In humans, narcolepsy is associated with a specific variant of the
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.[39] However, some studies suggest that the stimulatory effects of orexin on feeding may be due to general arousal without necessarily increasing overall food intake.[40]
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.[41] 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.[42][43] 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.[44]
Addiction
Preliminary research shows potential for orexin blockers in the treatment of cocaine, opioid, and alcohol addiction.[45][46][47] For example, lab rats given drugs which targeted the orexin system lost interest in alcohol despite being given free access in experiments.[48][49] 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.[50]
Studies of orexin involvement in nicotine addiction have had mixed results. For example, blocking the orexin-1 receptor with the selective
Lipid metabolism
Orexin-A (OXA) has been demonstrated to have a direct effect on an aspect of
Mood
High levels of orexin-A have been associated with happiness in human subjects, while low levels have been associated with sadness.[54] 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.[55]
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.[56]
Orexin neurons
Neurotransmitters
Orexinergic neurons have been shown to be sensitive to inputs from Group III
Orexinergic neurons can be differentiated into two groups based on connectivity and functionality. Orexinergic neurons in the 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.[72] 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.[73][74]
Orexin system dysfunction
Orexin/hypocretin system dysfunction might be associated with a variety of disorders and medical conditions.[75][76]
Takotsubo syndrome
Orexin/hypocretin system dysfunction has been proposed as a novel pathophysiological model of Takotsubo syndrome (acute failure syndrome).[77]
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.[78]
Clinical uses
The orexin/hypocretin system is the target of the insomnia medication
In 2016, the
In 2022, the European Medicines Agency authorized the use of daridorexant (Quviviq) for sleep initiation and maintenance disorders.[84]
Other potential uses
Intranasal orexin is able to increase cognition in primates, especially under sleep deprived situations,[85] which may provide an opportunity for the treatment of excessive daytime sleepiness.[86]
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.[87]
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.[72]
Evolution
Prepro-orexin | |||||||||
---|---|---|---|---|---|---|---|---|---|
Identifiers | |||||||||
Symbol | Orexin | ||||||||
SCOP2 | 1cq0 / SCOPe / SUPFAM | ||||||||
OPM protein | 1wso | ||||||||
|
The exon architecture of orexin is conserved in all vertebrates.[88]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000161610 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000045471 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ ISBN 9780387922713.
- ^ a b Stanford Center for Narcolepsy FAQ (retrieved 27-Mar-2012)
- S2CID 33215844.
- PMID 21034217.
- ^ ISBN 9781592599509.
- ^ PMID 26045032.
- ^ S2CID 16294729.
- PMID 9419374.
- ^ a b Extance A (2022-11-07). "The brain chemicals that control what we enjoy". chemistryworld.com. Royal Society of Chemistry. Retrieved 2023-04-04.
- ^ S2CID 2038246.
- PMID 8710940.
- PMID 11983761.
- ^ PMID 23508038.
- PMID 36713640.
- S2CID 243394088.
- PMID 14691055.
- PMID 10498827.
- PMID 21216246.
- PMID 36781929.
- PMID 27524625.
- PMID 22049437.
- PMID 21982708.
- PMID 31546102.
- PMID 9614245.
- PMID 12040064.
- S2CID 902666.
- S2CID 89799178.
- PMID 15254084.
- PMID 21034217.
- ^ Alexis Madrigal (2007-12-28). "Snorting a Brain Chemical Could Replace Sleep". Wired. Wired News, Condé Nast. Retrieved 2008-02-05.
- PMID 18160631.
- PMID 10984567.
- PMID 19412176.
- ^ "Narcolepsy is an autoimmune disorder, Stanford researcher says". EurekAlert. American Association for the Advancement of Science. 2009-05-03. Retrieved 2009-05-31.
- PMID 19008313.
- S2CID 39775146.
- S2CID 23346403.
- S2CID 40999737.
- S2CID 8932862.
- PMID 23508038.
- ^ "Neurotransmitter Orexin Associated With Pleasure And Reward Pathways In The Brain". ScienceDaily. Retrieved 2018-05-08.
- S2CID 4386257.
- PMID 19656173.
- ^ Helen Puttick (2006-12-26). "Hope in fight against alcoholism". The Herald. Archived from the original on 2012-02-10. Retrieved 2007-02-11.
- PMID 16751790.
- PMID 28620314.
- ^ "Blocking A Neuropeptide Receptor Decreases Nicotine Addiction". ScienceDaily LLC. 2008-12-01. Retrieved 2009-02-11.
- PMID 28296947.
- PMID 21505958.
- PMID 23462990.
- Lay summary in: "Is this peptide a key to happiness? Findings suggests possible new treatment for depression, other disorders". Science Daily (Press release). March 7, 2013.
- PMID 30087452.
- PMID 35203914.
- PMID 15044540.
- PMID 24391536.
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 ... 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. ... 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.
• 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 - 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.
- 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.
- PMID 17093123.
- PMID 18344611.
- PMID 15306649.
- PMID 15470140.
- PMID 16093397.
- PMID 15634779.
- PMID 16611835.
- S2CID 7888110.
- S2CID 18515164.
- S2CID 19452926.
- S2CID 45872346.
- ^ PMID 22813971.
- PMID 19815001.
- S2CID 9209963.
- PMID 33033776.
- PMID 35886210.
- PMID 36407467.
- PMID 36411777.
- ^ "BELSOMRA® (suvorexant) C-IV". Belsomra. Retrieved 2015-10-31.
- ^ Ventura J, ed. (2014-08-31). "FDA approves new type of sleep drug, Belsomra". Food and Drug Administration (FDA). Retrieved 2015-10-31.
- ^ "Dayvigo- lemborexant tablet, film coated". DailyMed. U.S. National Library of Medicine. Retrieved 30 September 2021.
- ^ ""Quviviq- daridorexant tablet" (PDF). fda.gov.
- ^ Clinical trial number NCT02785406 for "Role of the Orexin Receptor System in Stress, Sleep and Cocaine Use" at ClinicalTrials.gov
- PMID 25462194.
- PMID 18830438.
- PMID 15683135. Archived from the original(PDF) on 2016-03-03.
- S2CID 34333729.
External links
- orexins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- Compare Different Sleep Aids, National Sleep Foundation
- Orexin receptor antagonists: A new class of sleeping pill, National Sleep Foundation