|Anatomical terms of neuroanatomy|
The lateral hypothalamus (LH), also called the lateral hypothalamic area (LHA), contains the primary orexinergic nucleus within the hypothalamus that widely projects throughout the nervous system; this system of neurons mediates an array of cognitive and physical processes, such as promoting feeding behavior and arousal, reducing pain perception, and regulating body temperature, digestive functions, and blood pressure, among many others. Clinically significant disorders that involve dysfunctions of the orexinergic projection system include narcolepsy, motility disorders or functional gastrointestinal disorders involving visceral hypersensitivity (e.g., irritable bowel syndrome), and eating disorders.
The neurotransmitter glutamate and the endocannabinoids (e.g., anandamide) and the orexin neuropeptides orexin-A and orexin-B are the primary signaling neurochemicals in orexin neurons; pathway-specific neurochemicals include GABA, melanin-concentrating hormone, nociceptin, glucose, the dynorphin peptides, and the appetite-regulating peptide hormones leptin and ghrelin, among others. Notably, cannabinoid receptor 1 (CB1) is colocalized on orexinergic projection neurons in the lateral hypothalamus and many output structures, where the CB1 and orexin receptor 1 (OX1) receptors form the CB1–OX1 receptor heterodimer.
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The orexinergic projections from the lateral hypothalamus innervate the entirety of the remainder of the hypothalamus, with robust projections to the posterior hypothalamus, tuberomammillary nucleus (the histamine projection nucleus), the arcuate nucleus, and the paraventricular hypothalamic nucleus. In addition to the histaminergic nucleus, the orexin system also projects onto the ventral tegmental area dopamine nucleus, locus ceruleus noradrenergic nucleus, the serotonergic raphe nuclei, and cholinergic pedunculopontine nucleus and laterodorsal tegmental nucleus. The histaminergic, dopaminergic, serotonergic, noradrenergic, and cholinergic nuclei which the lateral hypothalamic orexin neurons project onto constitute the primary components of the ascending reticular activating system.
Other output regions include: the ventromedial hypothalamus, medial and lateral septal nuclei, central medial amygdala, zona incerta, periaqueductal gray matter, lateral habenula, diagonal band, substantia innominata (contains the nucleus basalis), stria terminalis, prefrontal cortex, various brain stem substructures, including the rostral ventromedial medulla, rostral ventrolateral medulla, nucleus ambiguus, solitary nucleus, spinal trigeminal nucleus, pontine micturition center, ventral respiratory group, and pontine respiratory group), area postrema, and dorsal nucleus of vagus nerve.
Cannabinoid receptor 1 (CB1) is colocalized on orexinergic projection neurons in the lateral hypothalamus and many output structures, where the CB1 and orexin receptor 1 (OX1) receptors physically and functionally join together to form the CB1–OX1 receptor heterodimer. There is substantial anatomical and functional overlap and systemic cross-talk between the endocannabinoid system and orexin system within the central nervous system.
Through the diverse outputs of the orexin system, the orexin neurons in the lateral hypothalamus mediate an array of functions. Two of the most commonly noted functions of orexin peptides in the lateral hypothalamus are the promotion of feeding behavior and arousal (i.e., wakefulness). More generally, the orexinergic neural projections of the lateral hypothalamus are involved in thermoregulation, regulating gastrointestinal motility and gastrointestinal function by way of the dorsal nucleus of the vagus nerve, reducing pain and nociception through several output structures (e.g., periaqueductal gray matter), modulating the rewarding property of stimuli through the ventral tegmental area projections and other outputs in the reward system, regulating energy homeostasis and neuroendocrine functions (e.g., HPA axis, HPG axis, and HPT axis) through other hypothalamic outputs, and regulating visceral functions (e.g., respiration, blood pressure, and urination) via a group of structures in the brain stem, among other functions.
The endocannabinoid system and the orexin system mediate many of the same cognitive and physical effects, and a significant overlap in their function and localization has been noted in a 2013 medical review; the CB1–OX1 receptor heterodimer produces a 100-fold amplification of the potency of the orexin receptor 1-mediated ERK pathway signaling. Unique functional interactions have been noted as well, such as an OX1-induced CB1 pressor response in the rostral ventrolateral medulla.
Narcolepsy is associated with a marked reduction in the number of orexinergic projection neurons from the lateral hypothalamus and very low orexin peptides in cerebrospinal fluid. This has been identified as the mechanism responsible for narcoleptic symptoms.
Evidence suggest that OX1 neurons that synapse onto the dorsal nucleus of the vagus nerve and parts of the brain stem may play a role in the pathophysiology of chronic pain and visceral hypersensitivity in functional gastrointestinal disorders.
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- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 6: Widely Projecting Systems: Monoamines, Acetylcholine, and Orexin". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 179. ISBN 9780071481274.
Orexinergic projections in the CNS. Orexin neurons with cell bodies in the lateral hypothalamic area (LHA) and posterior hypothalamus (PH) project throughout the brain (excluding the cerebellum) with dense projections to the noradrenergic locus ceruleus (LC), histaminergic tuberomamillary nucleus (TMN), serotonergic raphe nuclei, cholinergic laterodorsal and pedunculopontine nuclei (LDT and PPT), and the dopaminergic ventral tegmental area (VTA). ... Orexin neurons project to and activate monoaminergic and cholinergic neurons involved in the maintenance of a long "awake" period. Lack of orexin produces narcolepsy (Chapter 12). Orexin neurons are regulated by peripheral mediators that carry information about energy balance, including glucose, leptin, and ghrelin. They also receive inputs from limbic structures. Orexin neurons are, therefore, in a position not only to regulate sleep-wake cycles, but also to respond to significant environmental and metabolic signals. Accordingly, orexin plays a role in the regulation of energy homeostasis, reward, and perhaps more generally in emotion.
- Li J, Hu Z, de Lecea L (January 2014). "The hypocretins/orexins: integrators of multiple physiological functions". British Journal of Pharmacology. 171 (2): 332–50. doi:10.1111/bph.12415. PMC 3904255. PMID 24102345.
Orexin neurons are excitatory, express the vesicular glutamate transporter VGLUT2 (Rosin et al., 2003), and also produce dynorphin ... The analgesic properties of orexin peptides have been well-established ... The involvement of orexin in pain is also supported by clinical observations, which have shown there is an association between changes in the Ox receptors and headaches (see below) (Rainero et al., 2004) and a recent multicentre case-control study revealed that chronic pain is more common in patients with narcolepsy with cataplexy than in the controls ... The orexin system has also been found to effect visceral functions, in addition to its roles in energy homeostasis and endocrine function, mentioned previously. ... orexin excites MCH neurons (van den Pol et al., 2004) and inhibits ventral medial hypothalamic (VMH) glucoreceptors to enhance feeding behaviours (Shiraishi et al., 2000). Moreover, a recent study demonstrated that the area postrema and nucleus of the tractus solitarius (NTS) are necessary for orexin-mediated hyperphagia ... However, i.v. injections of orexin-A have no effect on sympathetic activity (Matsumura et al., 2001), suggesting that the cardiac effects of orexin are mediated centrally. Consistently, microinjections of orexin-A into the rostral ventrolateral medulla (Huang et al., 2010) or rostral ventromedial medulla (Ciriello and de Oliveira, 2003) elicit cardiovascular excitatory responses through the activation of both OX1 and OX2 receptors (Huang et al., 2010).
However, orexin-A signalling in the nucleus ambiguus (NA) (de Oliveira and Ciriello, 2003) and subfornical organ (Smith et al., 2007) has been shown to produce bradycardia responses ... Moreover, activation of OX1 receptors in the dorsal motor nucleus of the vagus results in facilitation of vagal pancreatic efferent nerve activities (Wu et al., 2004), stimulating pancreatic exocrine secretion (Miyasaka et al., 2002). Administration of orexin-A, i.a., increases duodenal secretion in normal fed but not in fasted animals, by an effect that is independent of cholinergic pathways (Flemstrom et al., 2003; Bengtsson et al., 2007). In addition, orexin-A can modify gastrointestinal motility, including gastric emptying, gastric interdigestive motility (Naslund et al., 2002; Ehrstrom et al., 2005a,b2005b; Bulbul et al., 2010), and enteric peristalsis (Satoh et al., 2006), as well as colonic motility ...
The presence of orexin-A and its receptors has been shown in human kidneys and urine ... These findings are supported by results from physiological studies, which demonstrated that orexin-A is involved in the pelvic-urethral reflex (Peng et al., 2008) and the micturition reflex
- Flores A, Maldonado R, Berrendero F (December 2013). "Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far". Frontiers in Neuroscience. 7: 256. doi:10.3389/fnins.2013.00256. PMC 3868890. 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
- Okumura T, Nozu T, Kumei S, Takakusaki K, Miyagishi S, Ohhira M (February 2015). "Antinociceptive action against colonic distension by brain orexin in conscious rats". Brain Research. 1598: 12–7. doi:10.1016/j.brainres.2014.12.021. PMID 25527398. S2CID 7239191.
With regard to gastrointestinal functions, orexin-A acts centrally to regulate gastrointestinal functions such as gastric and pancreatic secretion, and gastrointestinal motility. ... Little is, however, known about a role of central orexin in visceral sensation. ... These results suggest for the first time that orexin-A specifically acts centrally in the brain to enhance antinociceptive response to colonic distension. We would furthermore suggest that endogenous orexin-A indeed mediates the antinociceptive effect of morphine on visceral sensation through the orexin 1 receptors. All these evidence might indicate that brain orexin plays a role in the pathophysiology of functional gastrointestinal disorders such as irritable bowel syndrome because visceral hypersensitivity of the gut is considered to play a vital role in the diseases.
- Messina G, Dalia C, Tafuri D, Monda V, Palmieri F, Dato A, Russo A, De Blasio S, Messina A, De Luca V, Chieffi S, Monda M (2014). "Orexin-A controls sympathetic activity and eating behavior". Frontiers in Psychology. 5: 997. doi:10.3389/fpsyg.2014.00997. PMC 4157463. PMID 25250003.
Orexins promote both arousal and feeding (Sweet et al., 1999). ... Orexin-A also influences body temperature. In fact, an ICV administration of orexin-A induces an increase in firing rate of the sympathetic nerves to BAT, accompanied with a rise in BAT and colonic temperatures (Monda et al., 2001).
- Watkins BA, Kim J (2014). "The endocannabinoid system: directing eating behavior and macronutrient metabolism". Frontiers in Psychology. 5: 1506. doi:10.3389/fpsyg.2014.01506. PMC 4285050. PMID 25610411.
CB1 is present in neurons of the enteric nervous system and in sensory terminals of vagal and spinal neurons in the gastrointestinal tract (Massa et al., 2005). Activation of CB1 is shown to modulate nutrient processing, such as gastric secretion, gastric emptying, and intestinal motility. ... CB1 is shown to co-localize with the food intake inhibiting neuropeptide, corticotrophin-releasing hormone, in the paraventricular nucleus of the hypothalamus, and with the two orexigenic peptides, melanin-concentrating hormone in the lateral hypothalamus and with pre-pro-orexin in the ventromedial hypothalamus (Inui, 1999; Horvath, 2003). CB1 knockout (KO) mice showed higher levels of CRH mRNA, suggesting that hypothalamic EC receptors are involved in energy balance and may be able to mediate food intake (Cota et al., 2003). ... The ECS works through many anorexigenic and orexigenic pathways where ghrelin, leptin, adiponectin, endogenous opioids, and corticotropin-releasing hormones are involved (Viveros et al., 2008).
- Sakurai N (2006). Seiji T (ed.). The orexin/hypocretin system physiology and pathophysiology. Totowa, N.J: Humana Press. pp. 25–35. ISBN 9781592599509. Retrieved 19 July 2015.
- Thompson MD, Xhaard H, Sakurai T, Rainero I, Kukkonen JP (2014). "OX1 and OX2 orexin/hypocretin receptor pharmacogenetics". Frontiers in Neuroscience. 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.
- Jäntti MH, Mandrika I, Kukkonen JP (March 2014). "Human orexin/hypocretin receptors form constitutive homo- and heteromeric complexes with each other and with human CB1 cannabinoid receptors". Biochemical and Biophysical Research Communications. 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.
- Reppucci CJ, Petrovich GD (July 2016). "Organization of connections between the amygdala, medial prefrontal cortex, and lateral hypothalamus: a single and double retrograde tracing study in rats". Brain Structure & Function. 221 (6): 2937–62. doi:10.1007/s00429-015-1081-0. PMC 4713378. PMID 26169110.
- Wright A. "Limbic System: Amygdala". In Byrne JH (ed.). Homeostasis and Higher Brain Function. Neuroscience Online. University of Texas Health Science Center at Houston.
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 12: Sleep and Arousal". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York, USA: McGraw-Hill Medical. p. 295. ISBN 9780071481274.
The RAS is a complex structure consisting of several different circuits including the four monoaminergic pathways ... The norepinephrine pathway originates from the locus ceruleus (LC) and related brainstem nuclei; the serotonergic neurons originate from the raphe nuclei within the brainstem as well; the dopaminergic neurons originate in ventral tegmental area (VTA); and the histaminergic pathway originates from neurons in the tuberomammillary nucleus (TMN) of the posterior hypothalamus. As discussed in Chapter 6, these neurons project widely throughout the brain from restricted collections of cell bodies. Norepinephrine, serotonin, dopamine, and histamine have complex modulatory functions and, in general, promote wakefulness. The PT in the brain stem is also an important component of the ARAS. Activity of PT cholinergic neurons (REM-on cells) promotes REM sleep. During waking, REM-on cells are inhibited by a subset of ARAS norepinephrine and serotonin neurons called REM-off cells. ... Orexin neurons are located in the lateral hypothalamus. They are organized in a widely projecting manner, much like the monoamines (Chapter 6), and innervate all of the components of the ARAS. They excite the REM-off monoaminergic neurons during wakefulness and the PT cholinergic neurons during REM sleep. They are inhibited by the VLPO neurons during NREM sleep.
- Li A, Nattie E (2014). "Orexin, cardio-respiratory function, and hypertension". Frontiers in Neuroscience. 8: 22. doi:10.3389/fnins.2014.00022. PMC 3921571. PMID 24574958.
In this review we focus on the role of orexin in cardio-respiratory functions and its potential link to hypertension. ... the central chemoreflex may be a causal link to the increased SNA and ABP in SHRs. Modulation of the orexin system could be a potential target in treating some forms of hypertension.
- Ibrahim BM, Abdel-Rahman AA (March 2014). "Cannabinoid receptor 1 signaling in cardiovascular regulating nuclei in the brainstem: A review". Journal of Advanced Research. 5 (2): 137–45. doi:10.1016/j.jare.2013.03.008. PMC 4294710. PMID 25685481.
- Ibrahim BM, Abdel-Rahman AA (October 2015). "A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats". Brain Research. 1622: 51–63. doi:10.1016/j.brainres.2015.06.011. PMC 4562882. PMID 26096126.
Orexin receptor 1 (OX1R) signaling is implicated in cannabinoid receptor 1 (CB1R) modulation of feeding. Further, our studies established the dependence of the central CB1R-mediated pressor response on neuronal nitric oxide synthase (nNOS) and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation in the RVLM. We tested the novel hypothesis that brainstem orexin-A/OX1R signaling plays a pivotal role in the central CB1R-mediated pressor response. Our multiple labeling immunofluorescence findings revealed co-localization of CB1R, OX1R and the peptide orexin-A within the C1 area of the rostral ventrolateral medulla (RVLM). Activation of central CB1R following intracisternal (i.c.) WIN55,212–2 (15μg/rat) in conscious rats caused significant increases in BP and orexin-A level in RVLM neuronal tissue. Additional studies established a causal role for orexin-A in the central CB1R-mediated pressor response
- Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 12: Sleep and Arousal". In Sydor A, Brown RY (eds.). Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. pp. 294–296, 303. ISBN 9780071481274.
Most cases of narcolepsy in humans are not linked to mutations in the genes encoding orexin peptides or receptors, but are associated with significantly reduced, often undetectable, levels of orexin in cerebrospinal fluid and brain tissues. Together, the linkage of narcolepsy with HLA alleles, its peak and trough incidence among those born in March and September, respectively (suggesting an environmental influence during the fetal or perinatal period), and the loss of orexin neurons raise the interesting possibility that narcolepsy may be caused by an autoimmune mediated destruction of these neurons in analogy with the autoimmune destruction of insulin-secreting β-islet cells in type I diabetes. A search for small-molecule agonists at orexin receptors is underway and could lead to a treatment for narcolepsy.