Skip to main content
SpringerLink
Log in

Central functions of the orexinergic system

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

The neuropeptide orexin is synthesized by neurons exclusively located in the hypothalamus. However, these neurons send axons over virtually the entire brain and spinal cord and therefore constitute a unique central orexinergic system. It is well known that central orexin plays a crucial role in the regulation of various basic non-somatic and somatic physiological functions, including feeding, energy homeostasis, the sleep/wake cycle, reward, addiction, and neuroendocrine, as well as motor control. Moreover, the absence of orexin results in narcolepsy-cataplexy, a simultaneous somatic and non-somatic dysfunction. In this review, we summarize these central functions of the orexinergic system and associated diseases, and suggest that this system may hold a key position in somatic-non-somatic integration.

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. de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci U S A 1998, 95: 322–327.

    Article  PubMed  Google Scholar 

  2. 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 

  3. Broberger C, de Lecea L, Sutcliffe JG, Hokfelt T. Hypocretin/orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: relationship to the neuropeptide Y and agouti gene-related protein systems. J Comp Neurol 1998, 402: 460–474.

    Article  PubMed  CAS  Google Scholar 

  4. Cutler DJ, Morris R, Sheridhar V, Wattam TA, Holmes S, Patel S, et al. Differential distribution of orexin-A and orexin-B immunoreactivity in the rat brain and spinal cord. Peptides 1999, 20: 1455–1470.

    Article  PubMed  CAS  Google Scholar 

  5. 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 

  6. Kukkonen JP, Holmqvist T, Ammoun S, Akerman KE. Functions of the orexinergic/hypocretinergic system. Am J Physiol Cell Physiol 2002, 283: 1567–1591.

    Article  Google Scholar 

  7. Zhu JN, Yung WH, Kwok-Chong Chow B, Chan YS, Wang JJ. The cerebellar-hypothalamic circuits: potential pathways underlying cerebellar involvement in somatic-visceral integration. Brain Res Rev 2006, 52: 93–106.

    Article  PubMed  Google Scholar 

  8. Zhu JN, Wang JJ. The cerebellum in feeding control: possible function and mechanism. Cell Mol Neurobiol 2008, 28: 469–478.

    Article  PubMed  Google Scholar 

  9. Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nat Rev Neurosci 2007, 8: 171–181.

    Article  PubMed  CAS  Google Scholar 

  10. Tsujino N, Sakurai T. Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev 2009, 61: 162–176.

    Article  PubMed  CAS  Google Scholar 

  11. Smart D, Jerman JC, Brough SJ, Rushton SL, Murdock PR, Jewitt F, et al. Characterization of recombinant human orexin receptor pharmacology in a Chinese hamster ovary cell-line using FLIPR. Br J Pharmacol 1999, 128: 1–3.

    Article  PubMed  CAS  Google Scholar 

  12. 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 

  13. 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 

  14. Cluderay JE, Harrison DC, Hervieu GJ. Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul Pept 2002, 104: 131–144.

    Article  PubMed  CAS  Google Scholar 

  15. 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 

  16. van den Pol AN. Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 1999, 19: 3171–3182.

    PubMed  Google Scholar 

  17. Lund PE, Shariatmadari R, Uustare A, Detheux M, Parmentier M, Kukkonen JP, et al. The orexin oX1 receptor activates a novel Ca2+ influx pathway necessary for coupling to phosphor-lipase C. J Biol Chem 2000, 275: 30806–30812.

    Article  PubMed  CAS  Google Scholar 

  18. Zhu Y, Miwa Y, Yamanaka A, Yada T, Shibahara M, Abe Y, et al. Orexin receptor type-1 couples exclusively to pertussis toxin-insensitive G-proteins, while orexin receptor type-2 couples to both pertussis toxin-sensitive and -insensitive G-proteins. J Pharmacol Sci 2003, 92: 259–266.

    Article  PubMed  CAS  Google Scholar 

  19. Borgland SL, Taha SA, Sarti F, Fields HL, Bonci A. Orexin A in the VTA is critical for the induction of synaptic plasticity and behavioral sensitization to cocaine. Neuron 2006, 49: 589–601.

    Article  PubMed  CAS  Google Scholar 

  20. Chen XW, Mu Y, Huang HP, Guo N, Zhang B, Fan SY, et al. Hypocretin-1 potentiates NMDA receptor-mediated somatodendritic secretion from locus ceruleus neurons. J Neurosci 2008, 28: 3202–3208.

    Article  PubMed  CAS  Google Scholar 

  21. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 1999, 98: 437–451.

    Article  PubMed  CAS  Google Scholar 

  22. Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell 1999, 98: 365–376.

    Article  PubMed  CAS  Google Scholar 

  23. Hara J, Beuckmann CT, Nambu T, Willie JT, Chemelli RM, Sinton CM, et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 2001, 30: 345–354.

    Article  PubMed  CAS  Google Scholar 

  24. Willie JT, Chemelli RM, Sinton CM, Tokita S, Williams SC, Kisanuki YY, et al. Distinct narcolepsy syndromes in orexin receptor-2 and orexin null mice: molecular genetics dissection of Non-REM and REM sleep regulatory processes. Neuron 2003, 38: 715–730.

    Article  PubMed  CAS  Google Scholar 

  25. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000, 6: 991–997.

    Article  PubMed  CAS  Google Scholar 

  26. Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000, 27: 469–474.

    Article  PubMed  CAS  Google Scholar 

  27. Nishino S, Ripley B, Overeem S, Lammers GJ, Mignot E. Hypocretin (orexin) deficiency in human narcolepsy. Lancet 2000, 355: 39–40.

    Article  PubMed  CAS  Google Scholar 

  28. Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, et al. Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc Natl Acad Sci U S A 1999, 96: 10911–10916.

    Article  PubMed  CAS  Google Scholar 

  29. Bourgin P, Huitrón-Reséndiz S, Spier AD, Fabre V, Morte B, Criado JR, et al. Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 2000, 20: 7760–7765.

    PubMed  CAS  Google Scholar 

  30. Estabrooke IV, McCarthy MT, Ko E, Chou TC, Chemelli RM, Yanagisawa M, et al. Fos expression in orexin neurons varies with behavioral state. J Neurosci 2001, 21: 1656–1662.

    PubMed  CAS  Google Scholar 

  31. Yoshida Y, Fujiki N, Nakajima T, Ripley B, Matsumura H, Yoneda H, et al. Fluctuation of extracellular hypocretin-1 (orexin A) levels in the rat in relation to the light-dark cycle and sleep-wake activities. Eur J Neurosci 2001, 14: 1075–1081.

    Article  PubMed  CAS  Google Scholar 

  32. Lee MG, Hassani oK, Jones BE. Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 2005, 25: 6716–6720.

    Article  PubMed  CAS  Google Scholar 

  33. Nakamura T, Uramura K, Nambu T, Yada T, Goto K, Yanagisawa M, et al. Orexin-induced hyperlocomotion and stereotypy are mediated by the dopaminergic system. Brain Res 2000, 873: 181–187.

    Article  PubMed  CAS  Google Scholar 

  34. Brown RE, Sergeeva OA, Eriksson KS, Haas HL. Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline). J Neurosci 2002, 22: 8850–8859.

    PubMed  CAS  Google Scholar 

  35. 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 

  36. Yamanaka A, Tsujino N, Funahashi H, Honda K, Guan JL, Wang QP, et al. Orexins activate histaminergic neurons via the orexin 2 receptor. Biochem Biophys Res Commun 2002, 290: 1237–1245.

    Article  PubMed  CAS  Google Scholar 

  37. Mieda M, Yanagisawa M. Sleep, feeding, and neuropeptides: roles of orexins and orexin receptors. Curr opin Neurobiol 2002, 12: 339–345.

    Article  PubMed  CAS  Google Scholar 

  38. Eggermann E, Serafin M, Bayer L, Machard D, Saint-Mleux B, Jones BE, et al. Orexins/hypocretins excite basal forebrain cholinergic neurons. Neuroscience 2001, 108: 177–181.

    Article  PubMed  CAS  Google Scholar 

  39. Eriksson KS, Sergeeva O, Brown RE, Haas HL. Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus. J Neurosci 2001, 21: 9273–9279.

    PubMed  CAS  Google Scholar 

  40. Huang ZL, Qu WM, Li WD, Mochizuki T, Eguchi N, Watanabe T, et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 2001, 98: 9965–9970.

    Article  PubMed  CAS  Google Scholar 

  41. Willie JT, Chemelli RM, Sinton CM, Yanagisawa M. To eat or to sleep? orexin in the regulation of feeding and wakefulness. Annu Rev Neurosci 2001, 24: 429–458.

    Article  PubMed  CAS  Google Scholar 

  42. Yoshida K, McCormack S, Espana RA, Crocker A, Scammell TE. Afferents to the orexin neurons of the rat brain. J Comp Neurol 2006, 494: 845–861.

    Article  PubMed  Google Scholar 

  43. Matsuki T, Nomiyama M, Takahira H, Hirashima N, Kunita S, Takahashi S, et al. Selective loss of GABAB receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proc Natl Acad Sci U S A 2009, 106: 4459–4464.

    Article  PubMed  CAS  Google Scholar 

  44. Mileykovskiy BY, Kiyashchenko Li, Siegel JM. Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 2005, 46: 787–798.

    Article  PubMed  CAS  Google Scholar 

  45. Kiyashchenko Li, Mileykovskiy BY, Maidment N, Lam HA, Wu MF, John J, et al. Release of hypocretin (orexin) during waking and sleep states. J Neurosci 2002, 22: 5282–5286.

    PubMed  CAS  Google Scholar 

  46. Takakusaki K, Takahashi K, Saitoh K, Harada H, Okumura T, Kayama Y, et al. 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 

  47. Korotkova TM, Eriksson KS, Haas HL, Brown RE. Selective excitation of GABAergic neurons in the substantia nigra of the rat by orexin/hypocretin in vitro. Regul Pept 2002, 104: 83–89.

    Article  PubMed  CAS  Google Scholar 

  48. 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 

  49. Yu L, Zhang XY, Zhang J, Zhu JN, Wang JJ. Orexins excite neurons of the rat cerebellar nucleus interpositus via orexin 2 receptors in vitro. Cerebellum 2010, 9: 88–95.

    Article  PubMed  CAS  Google Scholar 

  50. Zhang J, Li B, Yu L, He YC, Li HZ, Zhu JN, et al. A role for orexin in central vestibular motor control. Neuron 2011, 69: 793–804.

    Article  PubMed  CAS  Google Scholar 

  51. Yamanaka A, Sakurai T, Katsumoto T, Yanagisawa M, Goto K. Chronic intracerebroventricular administration of orexin-A to rats increases food intake in daytime, but has no effect on body weight. Brain Res 1999, 849: 248–252.

    Article  PubMed  CAS  Google Scholar 

  52. Kotz CM. Integration of feeding and spontaneous physical activity: role for orexin. Physiol Behav 2006, 88: 294–301.

    Article  PubMed  CAS  Google Scholar 

  53. Haynes AC, Jackson B, Chapman H, Tadayyon M, Johns A, Porter RA, et al. A selective orexin-1 receptor antagonist reduces food consumption in male and female rats. Regul Pept 2000, 96: 45–51.

    Article  PubMed  CAS  Google Scholar 

  54. 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 

  55. Yamanaka A, Kunii K, Nambu T, Tsujino N, Sakai A, Matsuzaki I, et al. Orexin-induced food intake involves neuropeptide Y pathway. Brain Res 2000, 859: 404–409.

    Article  PubMed  CAS  Google Scholar 

  56. van den Top M, Nolan MF, Lee K, Richardson PJ, Buijs RM, Davies CH, et al. Orexins induce increased excitability and synchronization of rat sympathetic preganglionic neurones. J Physiol 2003, 549: 809–821.

    Article  PubMed  Google Scholar 

  57. Li Y, van den Pol AN. Differential target-dependent actions of coexpressed inhibitory dynorphin and excitatory hypocretin/orexin neuropeptides. J Neurosci 2006, 26: 13037–13047.

    Article  PubMed  CAS  Google Scholar 

  58. 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 Ca2+ 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 

  59. Ma X, Zubcevic L, Bruning JC, Ashcroft FM, Burdakov D. Electrical inhibition of identified anorexigenic POMC neurons by orexin/hypocretin. J Neurosci 2007, 27: 1529–1533.

    Article  PubMed  CAS  Google Scholar 

  60. Berthoud HR. Mind versus metabolism in the control of food intake and energy balance. Physiol Behav 2004, 81: 781–793.

    Article  PubMed  CAS  Google Scholar 

  61. Baldo BA, Gual-Bonilla L, Sijapati K, Daniel RA, Landry CF, Kelley AE. Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment. Eur J Neurosci 2004, 19: 376–386.

    Article  PubMed  Google Scholar 

  62. Novak CM, Levine JA. Daily intraparaventricular orexin-A treatment induces weight loss in rats. Obesity 2009, 178: 1493–1498.

    Article  Google Scholar 

  63. Zhang S, Zeitzer JM, Sakurai T, Nishino S, Mignot E. Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy. J Physiol 2007, 581: 649–663.

    Article  PubMed  Google Scholar 

  64. Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, et al. Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 2003, 38: 701–713.

    Article  PubMed  CAS  Google Scholar 

  65. Sellayah D, Bharaj P, Sikder D. Orexin is required for brown adipose tissue development, differentiation, and function. Cell Metab 2011, 14: 478–490.

    Article  PubMed  CAS  Google Scholar 

  66. Akimoto H, Honda Y, Takahashi Y. Pharmacotherapy in narcolepsy. Dis Nerv Syst 1960, 21: 704–706.

    PubMed  CAS  Google Scholar 

  67. Georgescu D, Zachariou V, Barrot M, Mieda M, Willie JT, Eisch AJ, et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 2003, 23: 3106–3111.

    PubMed  CAS  Google Scholar 

  68. Narita M, Nagumo Y, Hashimoto S, Narita M, Khotib J, Miyatake M, et al. Direct involvement of orexinergic systems in the activation of the mesolimbic dopamine pathway and related behaviors induced by morphine. J Neurosci 2006, 26: 398–405.

    Article  PubMed  CAS  Google Scholar 

  69. Fadel J, Deutch AY. Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area. Neuroscience 2002, 111: 379–387.

    Article  PubMed  CAS  Google Scholar 

  70. Korotkova TM, Sergeeva oA, Eriksson KS, Haas HL, Brown RE. Excitation of ventral tegmental area dopaminergic and nondopaminergic neurons by orexins/hypocretins. J Neurosci 2003, 23: 7–11.

    PubMed  CAS  Google Scholar 

  71. Boutrel B, Kenny PJ, Specio SE, Fardon RM, Markou A, Koob GF, et al. Role for hypocretin in mediating stress-induced reinstatement of cocaine-seeking behavior. Proc Natl Acad Sci U S A 2005, 102: 19168–19173.

    Article  PubMed  CAS  Google Scholar 

  72. Harris GC, Wimmer M, Aston-Jones G. A role for lateral hypothalamic orexin neurons in reward seeking. Nature 2005, 437: 556–559.

    Article  PubMed  CAS  Google Scholar 

  73. Lawrence AJ, Cowen MS, Yang HJ, Chen F, Oldfield B. The orexin system regulates alcohol-seeking in rats. Br J Pharmacol 2006, 148: 752–759.

    Article  PubMed  CAS  Google Scholar 

  74. Kuru M, Ueta Y, Serino R, Nakazato M, Yamamoto Y, Shibuya i, et al. Centrally administered orexin/hypocretin activates HPA axis in rats. Neuroreport 2000, 11: 1977–1980.

    Article  PubMed  CAS  Google Scholar 

  75. Lopez M, Seoane LM, Tovar S, Nogueiras R, Dieguez C, Senaris R. Orexin-A regulates growth hormone-releasing hormone mRNA content in a nucleus-specific manner and somatostatin mRNA content in a growth hormone-dependent fashion in the rat hypothalamus. Eur J Neurosci 2004, 19: 2080–2088.

    Article  PubMed  Google Scholar 

  76. Seoane LM, Tovar SA, Perez D, Mallo F, Lopez M, Senaris R, et al. Orexin A suppresses in vivo GH secretion. Eur J Endocrinol 2004, 150: 731–736.

    Article  PubMed  CAS  Google Scholar 

  77. Campbell RE, Grove KL, Smith MS. Gonadotropin-releasing hormone neurons coexpress receptor immunoreactivity immunoreactivity and receive direct contacts by orexin fibers. Endocrinology 2003, 144: 1542–1548.

    Article  PubMed  CAS  Google Scholar 

  78. Small CJ, Goubillon ML, Murray JF, Siddiqui A, Grimshaw SE, Young H, et al. Central orexin A has site-specific effects on luteinizing hormone release in female rats. Endocrinology 2003, 144: 3225–3236.

    Article  PubMed  CAS  Google Scholar 

  79. Kok SW, Roelfsema F, Overeem S, Lammers GJ, Frolich M, Meinders AE, et al. Pulsatile LH release is diminished, while FSH secretion is normal in hypocretin deficient narcoleptic men. Am J Physiol Endocrinol Metab 2004, 287: E630–E636.

    Article  PubMed  CAS  Google Scholar 

  80. Katafuchi T, Puthuraya KP, Yoshimatsu H, Oomura Y. Responses of rat lateral hypothalamic neuron activity to vestibular nuclei stimulation. Brain Res 1987, 400: 62–69.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biological Science and Technology and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, China

    Xiao-Yang Zhang, Lei Yu, Qian-Xing Zhuang, Jing-Ning Zhu & Jian-Jun Wang

Authors
  1. Xiao-Yang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lei Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian-Xing Zhuang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jing-Ning Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jian-Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jing-Ning Zhu or Jian-Jun Wang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, XY., Yu, L., Zhuang, QX. et al. Central functions of the orexinergic system. Neurosci. Bull. 29, 355–365 (2013). https://doi.org/10.1007/s12264-012-1297-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-012-1297-4

Keywords

Search

Navigation