Skip to main content
SpringerLink
Log in

Role of orexin in central regulation of gastrointestinal functions

  • Review
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Orexins are neuropeptides that are localized in neurons within the lateral hypothalamus and regulate feeding behavior. The lateral hypothalamus plays an important role in not only feeding but also in the central regulation of gut function. Along this line, accumulating evidence has shown that orexins act in the central nervous system to regulate gastrointestinal functions. The purpose of this review is to summarize recent relevant findings on brain orexins and the digestive system, and discuss the pathophysiological roles of these peptides. Centrally administered orexin or endogenously released orexin in the brain potently stimulates gastric acid secretion in rats. The vagal cholinergic pathway is involved in the orexin-induced stimulation of acid secretion. Because of its stimulatory action on feeding, it can be hypothesized that orexin in the brain is a candidate mediator of cephalic phase gastric secretion. In addition, brain orexin may be involved in the development of depression and functional gastrointestinal disorders, which are frequently accompanied by inhibition of gut function, because lack of orexin activity might cause the inhibition of gastric physiological processes and evoke a depressive state. These lines of evidence suggest that orexin in the brain is a potential molecular target for treatment of functional gastrointestinal disorders.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sakurai T, Amemiya A, Ishii M, Matsuzaki I, Chemelli RM, Tanaka H, et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 1998;92:573–585.

    Article  PubMed  CAS  Google Scholar 

  2. De Lecea L, Kilduff TS, Peyron C, Gao XB, Foye PE, Danielson RE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 1998;95:322–327.

    Article  PubMed  Google Scholar 

  3. Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, et al. Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 1998;18:9996–10015.

    PubMed  CAS  Google Scholar 

  4. Date Y, Ueta Y, Yamashita H, Yamaguchi S, Matsukura K, Kangawa T, et al. Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 1999;96:748–753.

    Article  PubMed  CAS  Google Scholar 

  5. Elias CF, Saper CB, Maratos-Flier E, Tritos NA, Lee C, Kelly J, et al. Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area. J Comp Neurol 1998;402:442–459.

    Article  PubMed  CAS  Google Scholar 

  6. Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K. Distribution of orexin neurons in the adult rat brain. Brain Res 1999;827:243–260.

    Article  PubMed  CAS  Google Scholar 

  7. Sakurai T. Roles of orexins and orexin receptors in central regulation of feeding behavior and energy homeostasis. CNS Neurol Disord Drug Targets 2006;5:313–325.

    Article  PubMed  CAS  Google Scholar 

  8. Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM. Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 1998;438:71–75.

    Article  PubMed  CAS  Google Scholar 

  9. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 2007;3:171–181.

    Article  CAS  Google Scholar 

  10. Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA. Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 2001;103:777–797.

    Article  PubMed  CAS  Google Scholar 

  11. Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, et al. Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 2001;435:6–25.

    Article  PubMed  CAS  Google Scholar 

  12. Oomura Y. Handbook of the hypothalamus, vol 2. Physiology of the hypothalamus. In: Morgane PJ, Panksepp J, editors. New York: Marcel Dekker; 1980. p. 557–620.

    Google Scholar 

  13. Bernardis LL, Bellinger LL. The lateral hypothalamic area revisited: neuroanatomy, body weight regulation, neuroendocrinology and metabolism. Neurosci Biobehav Rev 1993;17:141–193.

    Article  PubMed  CAS  Google Scholar 

  14. Yamada H, Okumura T, Motomura W, Kobayashi Y, Kohgo Y. Inhibition of food intake by central injection of anti-orexin antibody in fasted rats. Biochem Biophys Res Commun 2000;267:527–531.

    Article  PubMed  CAS  Google Scholar 

  15. Ida T, Nakahara K, Katayama T, Murakami N, Nakazato M. Effect of lateral cerebroventricular injection of the appetitestimulating neuropeptide, orexin and neuropeptide Y, on the various behavioral activities of rats. Brain Res 1999;821:526–529.

    Article  PubMed  CAS  Google Scholar 

  16. Lubkin M, Stricker-Krongrad A. Independent feeding and metabolic actions of orexins in mice. Biochem Biophys Res Commun 1998;253:241–245.

    Article  PubMed  CAS  Google Scholar 

  17. Kotz CM, Teske JA, Levine JA, Wang C. Feeding and activity induced by orexin A in the lateral hypothalamus in rats. Regul Pept 2002;104:27–32.

    Article  PubMed  CAS  Google Scholar 

  18. Thorpe AJ, Mullett MA, Wang C, Kotz CM. Peptides that regulate food intake: regional, metabolic, and circadian specificity of lateral hypothalamic orexin A feeding stimulation. Am J Physiol Regul Integr Comp Physiol 2003;284:R1409–1417.

    PubMed  CAS  Google Scholar 

  19. Thorpe AJ, Kotz CM. Orexin A in the nucleus accumbens stimulates feeding and locomotor activity. Brain Res 2005;1050:156–162.

    Article  PubMed  CAS  Google Scholar 

  20. Sweet DC, Levine AS, Billington CJ, Kotz CM. Feeding response to central orexins. Brain Res 1999;821:535–538.

    Article  PubMed  CAS  Google Scholar 

  21. Muroya S, Funahashi H, Yamanaka A, Kohno D, Uramura K, Nambu T, et al. Orexins (hypocretins) directly interact with neuropeptide Y, POMC and glucose-responsive neurons to regulate Ca 2+ signaling in a reciprocal manner to leptin: orexigenic neuronal pathways in the mediobasal hypothalamus. Eur J Neurosci 2004;19:1524–1534.

    Article  PubMed  Google Scholar 

  22. Taché Y, Yang H. Brain regulation of gastric acid secretion by peptides. Sites and mechanisms of action. Ann N Y Acad Sci 1990;597:128–145.

    Article  PubMed  Google Scholar 

  23. Takahashi N, Okumura T, Yamada H, Kohgo Y. Stimulation of gastric acid secretion by centrally administered orexin-A in conscious rats. Biochem Biophys Res Commun 1999;254:623–627.

    Article  PubMed  CAS  Google Scholar 

  24. Okumura T, Fukagawa K, Tso P, Taylor IL, Pappas TN. Intracisternal injection of apolipoprotein A-IV inhibits gastric secretion in pylorus-ligated conscious rats. Gastroenterology 1994;107:1861–1864.

    PubMed  CAS  Google Scholar 

  25. Okumura T, Uehara A, Okamura K, Takasugi Y, Namiki M. Inhibition of gastric pepsin secretion by peripherally or centrally injected interleukin-1 in rats. Biochem Biophys Res Commun 1990;167:956–961.

    Article  PubMed  CAS  Google Scholar 

  26. Okumura T, Uehara A, Tsuji K, Taniguchi Y, Kitamori S, Shibata Y, et al. Central nervous system action of basic fibroblast growth factor: inhibition of gastric acid and pepsin secretion. Biochem Biophys Res Commun 1991;175:527–531.

    Article  PubMed  CAS  Google Scholar 

  27. Okumura T, Yamada H, Motomura W, Kohgo Y. A novel anorectic chemical, cocaine-amphetamine-regulated transcript (CART), acts in the central nervous system to inhibit gastric acid secretion via brain CRF system. Endocrinology 2000;141:2854–2860.

    Article  PubMed  CAS  Google Scholar 

  28. Misher A, Brooks FP. Electrical stimulation of hypothalamus and gastric secretion in the albino rat. Am J Physiol 1966;211:403–406.

    PubMed  CAS  Google Scholar 

  29. Grijalva CV, Novin D. The role of the hypothalamus and dorsal vagal complex in gastrointestinal function and pathophysiology. Ann N Y Acad Sci 1990;597:207–222.

    Article  PubMed  CAS  Google Scholar 

  30. Colin-Jones DG, Himsworth RL. The location of the chemoreceptor controlling gastric acid secretion during hypoglycaemia. J Physiol 1970;206:397–409.

    PubMed  CAS  Google Scholar 

  31. Kimani SN, Zawoiski EJ. Effect of bilateral intracerebral ablation on the gastric secretory response to insulin-induced hypoglycemia. Exp Neurol 1974;45:491–502.

    Article  PubMed  CAS  Google Scholar 

  32. Davis RA, Brooks FP, Steckel DC. Gastric secretory changes after anterior hypothalamic lesions. Am J Physiol 1968;5:600–604.

    Google Scholar 

  33. Okumura T, Takeuchi S, Motomura W, Yamada H, Egashira S, Asahi S, et al. Requirement of intact disulfide bonds in orexin-Ainduced stimulation of gastric acid secretion that is mediated by OX1 receptor activation. Biochem Biophys Res Commun 2001;280:976–981.

    Article  PubMed  CAS  Google Scholar 

  34. Kalia M, Sullivan JM. Brainstem projections of sensory and motor components of the vagus nerve in the rat. J Comp Neurol 1982;211:248–265.

    Article  PubMed  CAS  Google Scholar 

  35. Okumura T, Namiki M. Vagal motor neurons innervating the stomach are site-specifically organized in the dorsal motor nucleus of the vagus nerve in rats. J Auton Nerv Syst 1990;29:157–162.

    Article  PubMed  CAS  Google Scholar 

  36. Harrison TA, Chen CT, Dun NJ, Chang JK. Hypothalamic orexin A-immunoreactive neurons project to the rat dorsal medulla. Neurosci Lett 1999;273:17–20.

    Article  PubMed  CAS  Google Scholar 

  37. Berk ML, Finkelstein JA. Efferent connections of the lateral hypothalamic area of the rat: an autoradiographic investigation. Brain Res Bull 1982;8:511–526.

    Article  PubMed  CAS  Google Scholar 

  38. Ricardo JA, Koh ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala, and other forebrain structures in the rat. Brain Res 1978;153:1–26.

    Article  PubMed  CAS  Google Scholar 

  39. Krowicki ZK, Burmeister MA, Berthoud HR, Schllion RT, Fucks K, Hornby PJ. Orexins in rat dorsal motor nucleus of the vagus potently stimulate gastric motor function. Am J Physiol 2002;283:1–15.

    Google Scholar 

  40. Hwang LL, Chen CT, Dun NJ. Mechanisms of orexin-induced depolarizations in rat dorsal motor nucleus of vagus neurones in vitro. J Physiol 2001;537:511–520.

    Article  PubMed  CAS  Google Scholar 

  41. Grabauskas G, Moises HC. Gastrointestinal-projecting neurones in the dorsal motor nucleus of the vagus exhibit direct and viscerotopically organized sensitivity to orexin. J Physiol 2003;549:37–56.

    Article  PubMed  CAS  Google Scholar 

  42. Rodgers RJ, Halford JC, Nunes de Souza RL, Canto de Souza AL, Piper DC, Arch JR, et al. SB-334867, a selective orexin-1 receptor antagonist, enhances behavioural satiety and blocks the hyperphagic effect of orexin-A in rats. Eur J Neurosci 2001;13:1444–1452.

    Article  PubMed  CAS  Google Scholar 

  43. Smart D, Sabido-David C, Brough SJ, Jewitt F, Johns A, Porter RA, et al. SB-334867-A: the first selective orexin-1 receptor antagonist. Br J Pharmacol 2001;132:1179–1182.

    Article  PubMed  CAS  Google Scholar 

  44. Soffin EM, Evans M, Gill CH, Harries MH, Benham CD, Davies CH. SB-334867-A antagonises orexin mediated excitation in the locus coeruleus. Neuropharmacology 2002;42:127–133.

    Article  PubMed  CAS  Google Scholar 

  45. Ducroc R, Voisin T, El Firar A, Laburthe M. Orexins control intestinal glucose transport by distinct neuronal, endocrine, and direct epithelial pathways. Diabetes 2007;56:2494–2500.

    Article  PubMed  CAS  Google Scholar 

  46. Yamada H, Takahashi N, Tanno S, Nagamine M, Takakusaki K, Okumura T. A selective orexin-1 receptor antagonist, SB334867, blocks 2-DG-induced gastric acid secretion in rats. Neurosci Lett 2005;376:137–142.

    Article  PubMed  CAS  Google Scholar 

  47. Colin-Jones DG, Himsworth RL. The location of the chemoreceptor controlling gastric acid secretion during hypoglycaemia. J Physiol 1970;206:397–409.

    PubMed  CAS  Google Scholar 

  48. Duke WW, Hirschowitz BI, Sachs G. Vagal stimulation of gastric secretion in man by 2-deoxy-D-glucose. Lancet 1965;2:871–876.

    Article  PubMed  CAS  Google Scholar 

  49. Cai XJ, Evans ML, Lister CA, Leslie RA, Arch JR, Wilson S, et al. Hypoglycemia activates orexin neurons and selectively increases hypothalamic orexin-B levels: responses inhibited by feeding and possibly mediated by the nucleus of the solitary tract. Diabetes 2001;50:105–112.

    Article  PubMed  CAS  Google Scholar 

  50. Brodows RG, Pi-Sunyer FX, Campbell RG. Neural control of counter-regulatory events during glucopenia in man. J Clin Invest 1973;52:1841–1844.

    Article  PubMed  CAS  Google Scholar 

  51. Briski KP, Sylvester PW. Hypothalamic orexin-A-immunopositive neurons express Fos in response to central glucopenia. Neuroreport 2001;12:531–534.

    Article  PubMed  CAS  Google Scholar 

  52. Pavlov I. Lectures on the work of the digestive glands. London: Griffin; 1910.

    Google Scholar 

  53. Vijayan E, McCann SM. Suppression of feeding and drinking activity in rats following intraventricular injection of thyrotropin releasing hormone (TRH). Endocrinology 1977;100:1727–17230.

    Article  PubMed  CAS  Google Scholar 

  54. Lin MT, Chu PC, Leu SY. Effects of TSH, TRH, LH and LHRH on thermoregulation and food and water intake in the rat. Neuroendocrinology 1983;37:206–211.

    Article  PubMed  CAS  Google Scholar 

  55. Debas HT. Physiology of the gastrointestinal tract. In: Johnson LR, editor. New York: Raven Press; 1987. p. 931–945.

    Google Scholar 

  56. Mori S, Matsuyama K, Kohyama J, Kobayashi Y, Takakusaki K. Neuronal constituents of postural and locomotor control systems and their interactions in cats. Brain Dev 1992;14:S109–120.

    PubMed  Google Scholar 

  57. Takakusaki K, Takahashi K, Saitoh K, Harada H, Okumura T, Koyama Y. Orexinergic projections to the midbrain mediate alternation of emotional behavioral states from locomotion to cataplexy. J Physiol 2005;568:1003–1020.

    Article  PubMed  CAS  Google Scholar 

  58. Sinnamon HM. Preoptic and hypothalamic neurons and the initiation of locomotion in the anesthetized rat. Prog Neurobiol 1993;41:323–344.

    Article  PubMed  CAS  Google Scholar 

  59. Grillner S. The motor infrastructure: from ion channels to neuronal networks. Nat Rev Neurosci 2003;4:573–586.

    Article  PubMed  CAS  Google Scholar 

  60. Kobashi M, Furudono Y, Matsuo R, Yamamoto T. Central orexin facilitates gastric relaxation and contractility in rats. Neurosci Lett 200;332:171–174.

  61. Azpiroz F, Malagelada JR. Physiological variations in canine gastric tone measured by an electronic barostat. Am J Physiol 1985;248:G229–37.

    PubMed  CAS  Google Scholar 

  62. Miyasaka K, Masuda M, Kanai S, Satom N, Kurosawa M, Funakoshi A. Central Orexin-A stimulates pancreatic exocrine secretion via the vagus. Pancreas 2002;25:400–404.

    Article  PubMed  Google Scholar 

  63. Wu X, Gao J, Yan J, Owyang C, Li Y. Hypothalamus-brain stem circuitry responsible for vagal efferent signaling to the pancreas evoked by hypoglycemia in rat. J Neurophysiol 2004;91:1734–1747.

    Article  PubMed  Google Scholar 

  64. Yamada H, Tanno S, Takakusaki K, Okumura T. Intracisternal injection of orexin-A prevents ethanol-induced gastric mucosal damage in rats. J Gastroenterol 2007;42;336–341.

    Article  PubMed  CAS  Google Scholar 

  65. Farr SA, Banks WA, Kumar VB, Morley JE. Orexin-A-induced feeding is dependent on nitric oxide. Peptides 2005;26:759–765.

    Article  PubMed  CAS  Google Scholar 

  66. Zheng H, Patterson LM, Berthoud HR. Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function. J Comp Neurol 2005;485:127–142.

    Article  PubMed  CAS  Google Scholar 

  67. Horvath TL, Peyron C, Diano S, Ivanov A, Aston-Jones G, Kilduff TS, et al. Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 1999;415:145–159.

    Article  PubMed  CAS  Google Scholar 

  68. Wang QP, Koyama Y, Guan JL, Takahashi K, Kayama Y, Shioda S. The orexinergic synaptic innervation of serotonin-and orexin 1-receptor-containing neurons in the dorsal raphe nucleus. Regul Pept 2005;126:35–42.

    Article  PubMed  CAS  Google Scholar 

  69. Liu RJ, van den Pol AN, Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 2002;22:9453–9464.

    PubMed  CAS  Google Scholar 

  70. Muraki Y, Yamanaka A, Tsujino N, Kilduff TS, Goto K, Sakurai T. Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. J Neurosci 2004;24:7159–7166.

    Article  PubMed  CAS  Google Scholar 

  71. Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008;358:55–68.

    Article  PubMed  CAS  Google Scholar 

  72. Dugovic C, Solberg LC, Redei E, Van Reeth O, Turek FW. Sleep in the Wistar-Kyoto rat, a putative genetic animal model for depression. Neuroreport 2000;11:627–631.

    Article  PubMed  CAS  Google Scholar 

  73. Allard JS, Tizabi Y, Shaffery JP, Trouth CO, Manaye K. Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression. Neuropeptides 2004;38:311–315.

    Article  PubMed  CAS  Google Scholar 

  74. Lutter M, Krishnan V, Russo SJ, Jung S, McClung CA, Nestler EJ. Orexin signaling mediates the antidepressant-like effect of calorie restriction. J Neurosci 2008;28:3071–3075.

    Article  PubMed  CAS  Google Scholar 

  75. Brundin L, Björkqvist M, Petersén A, Träskman-Bendz L. Reduced orexin levels in the cerebrospinal fluid of suicidal patients with major depressive disorder. Eur Neuropsychopharmacol 2007;9:573–579.

    Article  CAS  Google Scholar 

  76. Drossman DA. The functional gastrointestinal disorders and the Rome II process. Gut 1999;45Suppl 2:1–5.

    Google Scholar 

  77. Kojima M, Kangawa K. Drug insight: the functions of ghrelin and its potential as a multitherapeutic hormone. Nat Clin Pract Endocrinol Metab 2006;2:80–88.

    Article  PubMed  CAS  Google Scholar 

  78. Suzuki H, Masaoka T, Hosoda H, Ota T, Minegishi Y, Nomura S, et al. Helicobacter pylori infection modifies gastric and plasma ghrelin dynamics in Mongolian gerbils. Gut 2004;53:187–194.

    Article  PubMed  CAS  Google Scholar 

  79. Fukuhara S, Suzuki H, Masaoka T, Arakawa M, Hosoda H, Minegishi Y, et al. Enhanced ghrelin secretion in rats with cysteamineinduced duodenal ulcers. Am J Physiol Gastrointest Liver Physiol 2005;289:G138–45.

    Article  PubMed  CAS  Google Scholar 

  80. Ohno K, Sakurai T. Orexin neuronal circuitry: role in the regulation of sleep and wakefulness. Front Neuroendocrinol 2008;29:70–87.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of General Medicine, Asahikawa Medical College, 2-1-1 Midorigaoka-Higashi, Asahikawa, 078-8510, Japan

    Toshikatsu Okumura

  2. Department of Physiology, Asahikawa Medical College, Asahikawa, Japan

    Kaoru Takakusaki

Authors
  1. Toshikatsu Okumura
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaoru Takakusaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Okumura, T., Takakusaki, K. Role of orexin in central regulation of gastrointestinal functions. J Gastroenterol 43, 652–660 (2008). https://doi.org/10.1007/s00535-008-2218-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-008-2218-1

Key words

Search

Navigation