Advertisement

Orexin and Central Modulation of Cardiovascular and Respiratory Function

  • Pascal Carrive
  • Tomoyuki Kuwaki
Chapter
Part of the Current Topics in Behavioral Neurosciences book series (CTBN, volume 33)

Abstract

Orexin makes an important contribution to the regulation of cardiorespiratory function. When injected centrally under anesthesia, orexin increases blood pressure, heart rate, sympathetic nerve activity, and the amplitude and frequency of respiration. This is consistent with the location of orexin neurons in the hypothalamus and the distribution of orexin terminals at all levels of the central autonomic and respiratory network. These cardiorespiratory responses are components of arousal and are necessary to allow the expression of motivated behaviors. Thus, orexin contributes to the cardiorespiratory response to acute stressors, especially those of a psychogenic nature. Consequently, upregulation of orexin signaling, whether it is spontaneous or environmentally induced, can increase blood pressure and lead to hypertension, as is the case for the spontaneously hypertensive rat and the hypertensive BPH/2J Schlager mouse. Blockade of orexin receptors will reduce blood pressure in these animals, which could be a new pharmacological approach for the treatment of some forms of hypertension. Orexin can also magnify the respiratory reflex to hypercapnia in order to maintain respiratory homeostasis, and this may be in part why it is upregulated during obstructive sleep apnea. In this pathological condition, blockade of orexin receptors would make the apnea worse. To summarize, orexin is an important modulator of cardiorespiratory function. Acting on orexin signaling may help in the treatment of some cardiovascular and respiratory disorders.

Keywords

Blood pressure Chemoreflex Heart rate Hypercapnia Hypocretin Obstructive sleep apnea Ox1R Ox2R Psychological stress Respiration Rostral ventrolateral medulla Schlager mouse SHR Sympathetic 

Notes

Acknowledgment

Supported by grants from the National Health of Medical Research Council of Australia and from the Ministry of Education, Science, Culture, and Sports in Japan.

Conflict of Interest

The research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References

  1. 1.
    Carter ME, Brill J, Bonnavion P, Huguenard JR, Huerta R, de Lecea L (2012) Mechanism for hypocretin-mediated sleep-to-wake transitions. Proc Natl Acad Sci U S A 109(39):E2635–E2644. doi: 10.1073/pnas.1202526109CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Saper CB, Scammell TE, Lu J (2005) Hypothalamic regulation of sleep and circadian rhythms. Nature 437(7063):1257–1263. doi: 10.1038/nature04284CrossRefPubMedGoogle Scholar
  3. 3.
    Mahler SV, Moorman DE, Smith RJ, James MH, Aston-Jones G (2014) Motivational activation: a unifying hypothesis of orexin/hypocretin function. Nat Neurosci 17(10):1298–1303. doi: 10.1038/nn.3810CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Sakurai T (2014) The role of orexin in motivated behaviours. Nat Rev Neurosci 15(11):719–731. doi: 10.1038/nrn3837CrossRefGoogle Scholar
  5. 5.
    Nambu T, Sakurai T, Mizukami K, Hosoya Y, Yanagisawa M, Goto K (1999) Distribution of orexin neurons in the adult rat brain. Brain Res 827(1–2):243–260Google Scholar
  6. 6.
    Peyron C, Tighe DK, van den Pol AN, de Lecea L, Heller HC, Sutcliffe JG, Kilduff TS (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18(23):9996–10015Google Scholar
  7. 7.
    Abrahams VC, Hilton SM, Zbrozyna A (1960) Active muscle vasodilation produced by stimulation of the brainstem: its significance in the defence reaction. J Physiol (London) 154:491–513Google Scholar
  8. 8.
    Hilton SM (1982) The defence-arousal system and its relevance for circulatory and respiratory control. J Exp Biol 100:159–174PubMedPubMedCentralGoogle Scholar
  9. 9.
    Kayaba Y, Nakamura A, Kasuya Y, Ohuchi T, Yanagisawa M, Komuro I, Fukuda Y, Kuwaki T (2003) Attenuated defense response and low basal blood pressure in orexin knockout mice. Am J Physiol 285(3):R581–R593. doi: 10.1152/ajpregu.00671.2002CrossRefGoogle Scholar
  10. 10.
    Smith OA, DeVito JL, Astley CA (1990) Neurons controlling cardiovascular responses to emotion are located in lateral hypothalamus-perifornical region. Am J Physiol 259:R943–R954PubMedGoogle Scholar
  11. 11.
    Carrive P (2011) Central circulatory control. Psychological stress and the defense reaction. In: Llewellyn-Smith IJ, Verberne A (eds) Central regulation of autonomic function, 2nd edn. Oxford University Press, New York, pp. 220–237Google Scholar
  12. 12.
    Rosin DL, Weston MC, Sevigny CP, Stornetta RL, Guyenet PG (2003) Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2. J Comp Neurol 465(4):593–603. doi: 10.1002/cne.10860CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Chou TC, Lee CE, Lu J, Elmquist JK, Hara J, Willie JT, Beuckmann CT, Chemelli RM, Sakurai T, Yanagisawa M, Saper CB, Scammell TE (2001) Orexin (hypocretin) neurons contain dynorphin. J Neurosci 21(19):RC168PubMedGoogle Scholar
  14. 14.
    Muschamp JW, Hollander JA, Thompson JL, Voren G, Hassinger LC, Onvani S, Kamenecka TM, Borgland SL, Kenny PJ, Carlezon Jr WA (2014) Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area. Proc Natl Acad Sci U S A 111(16):E1648–E1655PubMedPubMedCentralGoogle Scholar
  15. 15.
    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):322–327PubMedPubMedCentralGoogle Scholar
  16. 16.
    Sawai N, Ueta Y, Nakazato M, Ozawa H (2010) Developmental and aging change of orexin-A and -B immunoreactive neurons in the male rat hypothalamus. Neurosci Lett 468(1):51–55. doi: 10.1016/j.neulet.2009.10.061CrossRefPubMedGoogle Scholar
  17. 17.
    Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, Kageyama H, Kunita S, Takahashi S, Goto K, Koyama Y, Shioda S, Yanagisawa M (2005) Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. Neuron 46(2):297–308. doi: 10.1016/j.neuron.2005.03.010CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Yoshida K, Mccormack S, España RA, Crocker A, Scammell TE (2006) Afferents to the orexin neurons of the rat brain. J Comp Neurol 494(5):845–861. doi: 10.1002/cne.20859CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Pitkänen A, Savander V, Ledoux JE (1997) Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci 20(11):517–523PubMedGoogle Scholar
  20. 20.
    Saper CB (2004) Central autonomic nervous system. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier, San Diego, pp. 761–794Google Scholar
  21. 21.
    Bochorishvili G, Nguyen T, Coates MB, Viar KE, Stornetta RL, Guyenet PG (2014) The orexinergic neurons receive synaptic input from C1 cells in rats. J Comp Neurol 522(17):3834–3846. doi: 10.1002/cne.23643CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Karnani MM, Apergis-Schoute J, Adamantidis A, Jensen LT, de Lecea L, Fugger L, Burdakov D (2011) Activation of central orexin/hypocretin neurons by dietary amino acids. Neuron 72(4):616–629PubMedGoogle Scholar
  23. 23.
    Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T (2003) Hypothalamic orexin neurons regulate arousal according to energy balance in mice. Neuron 38(5):701–713PubMedGoogle Scholar
  24. 24.
    Baldo BA, Daniel RA, Berridge CW, Kelley AE (2003) Overlapping distributions of orexin/hypocretin- and dopamine-beta-hydroxylase immunoreactive fibers in rat brain regions mediating arousal, motivation, and stress. J Comp Neurol 464(2):220–237. doi: 10.1002/cne.10783CrossRefGoogle Scholar
  25. 25.
    Berthoud H-R, Patterson LM, Sutton GM, Morrison C, Zheng H (2005) Orexin inputs to caudal raphé neurons involved in thermal, cardiovascular, and gastrointestinal regulation. Histochem Cell Biol 123(2):147–156. doi: 10.1007/s00418-005-0761-xCrossRefPubMedGoogle Scholar
  26. 26.
    Ciriello J, de Oliveira CVR (2003) Cardiac effects of hypocretin-1 in nucleus ambiguus. Am J Physiol 284(6):R1611–R1620. doi: 10.1152/ajpregu.00719.2002CrossRefGoogle Scholar
  27. 27.
    Ciriello J, Li Z, de Oliveira CVR (2003) Cardioacceleratory responses to hypocretin-1 injections into rostral ventromedial medulla. Brain Res 991(1–2):84–95PubMedGoogle Scholar
  28. 28.
    Geerling JC, Mettenleiter TC, Loewy AD (2003) Orexin neurons project to diverse sympathetic outflow systems. Neuroscience 122(2):541–550PubMedGoogle Scholar
  29. 29.
    Lazarenko RM, Stornetta RL, Bayliss DA, Guyenet PG (2011) Orexin A activates retrotrapezoid neurons in mice. Respir Physiol Neurobiol 175(2):283–287. doi: 10.1016/j.resp.2010.12.003CrossRefPubMedGoogle Scholar
  30. 30.
    Liu X, Zeng J, Zhou A, Theodorsson E, Fahrenkrug J, Reinscheid RK (2011) Molecular fingerprint of neuropeptide S-producing neurons in the mouse brain. J Comp Neurol 519(10):1847–1866. doi: 10.1002/cne.22603CrossRefPubMedGoogle Scholar
  31. 31.
    Puskás N, Papp RS, Gallatz K, Palkovits M (2010) Interactions between orexin-immunoreactive fibers and adrenaline or noradrenaline-expressing neurons of the lower brainstem in rats and mice. Peptides 31(8):1589–1597. doi: 10.1016/j.peptides.2010.04.020CrossRefPubMedGoogle Scholar
  32. 32.
    Rosin DL, Chang DA, Guyenet PG (2006) Afferent and efferent connections of the rat retrotrapezoid nucleus. J Comp Neurol 499(1):64–89. doi: 10.1002/cne.21105CrossRefPubMedGoogle Scholar
  33. 33.
    Shahid IZ, Rahman AA, Pilowsky PM (2012) Orexin A in rat rostral ventrolateral medulla is pressor, sympatho-excitatory, increases barosensitivity and attenuates the somato-sympathetic reflex. Br J Pharmacol 165(7):2292–2303. doi: 10.1111/j.1476-5381.2011.01694.xCrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Smith BN, Davis SF, van den Pol AN, Xu W (2002) Selective enhancement of excitatory synaptic activity in the rat nucleus tractus solitarius by hypocretin 2. Neuroscience 115(3):707–714PubMedPubMedCentralGoogle Scholar
  35. 35.
    Tupone D, Madden CJ, Cano G, Morrison SF (2011) An orexinergic projection from perifornical hypothalamus to raphé pallidus increases rat brown adipose tissue thermogenesis. J Neurosci 31(44):15944–15955. doi: 10.1523/JNEUROSCI.3909-11.2011CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Young JK, Wu M, Manaye KF, Kc P, Allard JS, Mack SO, Haxhiu MA (2005) Orexin stimulates breathing via medullary and spinal pathways. J Appl Physiol 98(4):1387–1395. doi: 10.1152/japplphysiol.00914.2004CrossRefPubMedGoogle Scholar
  37. 37.
    Zhang JH, Sampogna S, Morales FR, Chase MH (2004) Distribution of hypocretin (orexin) immunoreactivity in the feline pons and medulla. Brain Res 995(2):205–217PubMedGoogle Scholar
  38. 38.
    Zheng H, Patterson LM, Berthoud H-R (2005) Orexin-A projections to the caudal medulla and orexin-induced c-Fos expression, food intake, and autonomic function. J Comp Neurol 485(2):127–142. doi: 10.1002/cne.20515CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Date Y, Mondal MS, Matsukura S, Nakazato M (2000) Distribution of orexin-A and orexin-B (hypocretins) in the rat spinal cord. Neurosci Lett 288(2):87–90PubMedGoogle Scholar
  40. 40.
    Llewellyn-Smith IJ, Martin CL, Marcus JN, Yanagisawa M, Minson JB, Scammell TE (2003) Orexin-immunoreactive inputs to rat sympathetic preganglionic neurons. Neurosci Lett 351(2):115–119PubMedGoogle Scholar
  41. 41.
    van den Pol AN (1999) Hypothalamic hypocretin (orexin): robust innervation of the spinal cord. J Neurosci 19(8):3171–3182PubMedGoogle Scholar
  42. 42.
    Fung SJ, Yamuy J, Sampogna S, Morales FR, Chase MH (2001) Hypocretin (orexin) input to trigeminal and hypoglossal motoneurons in the cat: a double-labeling immunohistochemical study. Brain Res 903(1–2):257–262PubMedGoogle Scholar
  43. 43.
    Volgin DV, Saghir M, Kubin L (2002) Developmental changes in the orexin 2 receptor mRNA in hypoglossal motoneurons. Neuroreport 13(4):433–436PubMedGoogle Scholar
  44. 44.
    de Oliveira CVR, Rosas-Arellano MP, Solano-Flores LP, Ciriello J (2003) Cardiovascular effects of hypocretin-1 in nucleus of the solitary tract. Am J Physiol 284(4):H1369–H1377. doi: 10.1152/ajpheart.00877.2002CrossRefGoogle Scholar
  45. 45.
    Kuwaki T, Zhang W (2010) Autonomic malfunctions in mice model of narcolepsy. In: Santos G, Villalba L (eds) Narcolepsy: symptoms, causes and diagnosis. Nova Science Publishers, Inc., New York, pp. 1–33Google Scholar
  46. 46.
    Kuwaki T (2011) Orexin links emotional stress to autonomic functions. Autonom Neurosci 161:20–27Google Scholar
  47. 47.
    Gotter AL, Webber AL, Coleman PJ, Renger JJ, Winrow CJ (2012) International union of basic and clinical pharmacology. LXXXVI. orexin receptor function, nomenclature and pharmacology. Pharmacol Rev 64(3):389–420. doi: 10.1124/pr.111.005546CrossRefPubMedGoogle Scholar
  48. 48.
    Leonard CS, Kukkonen JP (2014) Orexin/hypocretin receptor signalling: a functional perspective. Br J Pharmacol 171:294–313PubMedGoogle Scholar
  49. 49.
    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.2014.00057CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Lu XY, Bagnol D, Burke S, Akil H, Watson SJ (2000) Differential distribution and regulation of OX1 and OX2 orexin/hypocretin receptor messenger RNA in the brain upon fasting. Horm Behav 37(4):335–344. doi: 10.1006/hbeh.2000.1584CrossRefPubMedGoogle Scholar
  51. 51.
    Marcus JN, Aschkenasi CJ, Lee CE, Chemelli RM, Saper CB, Yanagisawa M, Elmquist JK (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435(1):6–25Google Scholar
  52. 52.
    Sunter D, Morgan I, Edwards CM, Dakin CL, Murphy KG, Gardiner J, Taheri S, Rayes E, Bloom SR (2001) Orexins: effects on behavior and localisation of orexin receptor 2 messenger ribonucleic acid in the rat brainstem. Brain Res 907(1–2):27–34PubMedGoogle Scholar
  53. 53.
    Trivedi P, Yu H, MacNeil DJ, Van der Ploeg LH, Guan XM (1998) Distribution of orexin receptor mRNA in the rat brain. FEBS Lett 438(1–2):71–75PubMedPubMedCentralGoogle Scholar
  54. 54.
    van den Top M, Nolan MF, Lee K, Richardson PJ, Buijs RM, Davies CH, Spanswick D (2003) Orexins induce increased excitability and synchronisation of rat sympathetic preganglionic neurones. J Physiol 549(Pt 3):809–821. doi: 10.1113/jphysiol.2002.033290CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Cluderay JE, Harrison DC, Hervieu GJ (2002) Protein distribution of the orexin-2 receptor in the rat central nervous system. Regul Pept 104(1–3):131–144PubMedGoogle Scholar
  56. 56.
    Greco MA, Shiromani PJ (2001) Hypocretin receptor protein and mRNA expression in the dorsolateral pons of rats. Brain Res Mol Brain Res 88(1–2):176–182PubMedGoogle Scholar
  57. 57.
    Hervieu GJ, Cluderay JE, Harrison DC, Roberts JC, Leslie RA (2001) Gene expression and protein distribution of the orexin-1 receptor in the rat brain and spinal cord. Neuroscience 103(3):777–797PubMedGoogle Scholar
  58. 58.
    Bäckberg M, Hervieu G, Wilson S, Meister B (2002) Orexin receptor-1 (OX-R1) immunoreactivity in chemically identified neurons of the hypothalamus: focus on orexin targets involved in control of food and water intake. Europ J Neurosci 15(2):315–328Google Scholar
  59. 59.
    Yamanaka A, Tabuchi S, Tsunematsu T, Fukazawa Y, Tominaga M (2010) Orexin directly excites orexin neurons through orexin 2 receptor. J Neurosci 30(38):12642–12652. doi: 10.1523/JNEUROSCI.2120-10.2010CrossRefPubMedGoogle Scholar
  60. 60.
    Beig MI, Horiuchi J, Dampney RAL, Carrive P (2015) Both Ox1R and Ox2R orexin receptors contribute to the cardiorespiratory response evoked from the perifornical hypothalamus. Clin Exp Pharmacol Physiol 42(10):1059–1067. doi: 10.1111/1440-1681.12461CrossRefPubMedGoogle Scholar
  61. 61.
    Ibrahim BM, Abdel-Rahman AA (2015) A pivotal role for enhanced brainstem Orexin receptor 1 signaling in the central cannabinoid receptor 1-mediated pressor response in conscious rats. Brain Res 1622:51–63. doi: 10.1016/j.brainres.2015.06.011CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Kukkonen JP (2012) Recent progress in orexin/hypocretin physiology and pharmacology. Biomol Concepts 3:447–463PubMedPubMedCentralGoogle Scholar
  63. 63.
    Ch’ng SS, Lawrence AJ (2015) Distribution of the orexin-1 receptor (OX1R) in the mouse forebrain and rostral brainstem: a characterisation of OX1R-eGFP mice. J Chem Neuroanat. doi: 10.1016/j.jchemneu.2015.03.002CrossRefPubMedGoogle Scholar
  64. 64.
    Darwinkel A, Stanić D, Booth LC, May CN, Lawrence AJ, Yao ST (2014) Distribution of orexin-1 receptor-green fluorescent protein- (OX1-GFP) expressing neurons in the mouse brain stem and pons: co-localization with tyrosine hydroxylase and neuronal nitric oxide synthase. Neuroscience 278:253–264. doi: 10.1016/j.neuroscience.2014.08.027CrossRefPubMedGoogle Scholar
  65. 65.
    Morairty SR, Revel FG, Malherbe P, Moreau J-L, Valladao D, Wettstein JG, Kilduff TS, Borroni E (2012) Dual hypocretin receptor antagonism is more effective for sleep promotion than antagonism of either receptor alone. PLoS One 7(7):e39131. doi: 10.1371/journal.pone.0039131CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Scammell TE, Winrow CJ (2011) Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 51:243–266. doi: 10.1146/annurev-pharmtox-010510-100528CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Steiner MA, Gatfield J, Brisbare-Roch C, Dietrich H, Treiber A, Jenck F, Boss C (2013) Discovery and characterization of ACT-335827, an orally available, brain penetrant orexin receptor type 1 selective antagonist. ChemMedChem 8(6):898–903. doi: 10.1002/cmdc.201300003CrossRefPubMedGoogle Scholar
  68. 68.
    Bonaventure P, Yun S, Johnson PL, Shekhar A, Fitz SD, Shireman BT, Lebold TP, Nepomuceno D, Lord B, Wennerholm M, Shelton J, Carruthers N, Lovenberg T, Dugovic C (2015) A selective orexin-1 receptor antagonist attenuates stress-induced hyperarousal without hypnotic effects. J Pharmacol Exp Ther 352(3):590–601. doi: 10.1124/jpet.114.220392CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    McElhinny CJ, Lewin AH, Mascarella SW, Runyon S, Brieaddy L, Carroll FI (2012) Hydrolytic instability of the important orexin 1 receptor antagonist SB-334867: possible confounding effects on in vivo and in vitro studies. Bioorg Med Chem Lett 22(21):6661–6664. doi: 10.1016/j.bmcl.2012.08.109CrossRefGoogle Scholar
  70. 70.
    Hirose M, Egashira S, Goto Y, Hashihayata T, Ohtake N, Iwaasa H, Hata M, Fukami T, Kanatani A, Yamada K (2003) N-acyl 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline: the first orexin-2 receptor selective non-peptidic antagonist. Org Med Chem Lett 13(24):4497–4499Google Scholar
  71. 71.
    Malherbe P, Borroni E, Gobbi L, Knust H, Nettekoven M, Pinard E, Roche O, Rogers-Evans M, Wettstein JG, Moreau J-L (2009) Biochemical and behavioural characterization of EMPA, a novel high-affinity, selective antagonist for the OX(2) receptor. Br J Pharmacol 156(8):1326–1341. doi: 10.1111/j.1476-5381.2009.00127.xCrossRefPubMedPubMedCentralGoogle Scholar
  72. 72.
    Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, Aissaoui H, Flores S, Mueller C, Nayler O, Van Gerven J, De Haas SL, Hess P, Qiu C, Buchmann S, Scherz M, Weller T, Fischli W, Clozel M, Jenck F (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13(2):150–155. doi: 10.1038/nm1544CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Malherbe P, Borroni E, Pinard E, Wettstein JG, Knoflach F (2009) Biochemical and electrophysiological characterization of almorexant, a dual orexin 1 receptor (OX1)/orexin 2 receptor (OX2) antagonist: comparison with selective OX1 and OX2 antagonists. Mol Pharmacol 76(3):618–631. doi: 10.1124/mol.109.055152CrossRefPubMedGoogle Scholar
  74. 74.
    Asahi S, Egashira S-i, Matsuda M, Iwaasa H, Kanatani A, Ohkubo M, Ihara M, Morishima H (2003) Development of an orexin-2 receptor selective agonist, [Ala(11), D-Leu(15)]orexin-B. Bioorg Med Chem Lett 13(1):111–113Google Scholar
  75. 75.
    Bastianini S, Silvani A, Berteotti C, Elghozi J-L, Franzini C, Lenzi P, Lo Martire V, Zoccoli G (2011) Sleep related changes in blood pressure in hypocretin-deficient narcoleptic mice. Sleep 34(2):213–218PubMedPubMedCentralGoogle Scholar
  76. 76.
    Zhang W, Sakurai T, Fukuda Y, Kuwaki T (2006) Orexin neuron-mediated skeletal muscle vasodilation and shift of baroreflex during defense response in mice. Am J Physiol 290(6):R1654–R1663. doi: 10.1152/ajpregu.00704.2005CrossRefGoogle Scholar
  77. 77.
    Shirasaka T, Nakazato M, Matsukura S, Takasaki M, Kannan H (1999) Sympathetic and cardiovascular actions of orexins in conscious rats. Am J Physiol 277(6 Pt 2):R1780–R1785PubMedGoogle Scholar
  78. 78.
    Samson WK, Gosnell B, Chang JK, Resch ZT, Murphy TC (1999) Cardiovascular regulatory actions of the hypocretins in brain. Brain Res 831(1–2):248–253PubMedGoogle Scholar
  79. 79.
    Chen CT, Hwang LL, Chang JK, Dun NJ (2000) Pressor effects of orexins injected intracisternally and to rostral ventrolateral medulla of anesthetized rats. Am J Physiol 278(3):R692–R697Google Scholar
  80. 80.
    Shahid IZ, Rahman AA, Pilowsky PM (2011) Intrathecal orexin A increases sympathetic outflow and respiratory drive, enhances baroreflex sensitivity and blocks the somato-sympathetic reflex. Br J Pharmacol 162(4):961–973. doi: 10.1111/j.1476-5381.2010.01102.xCrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Hirota K, Kushikata T, Kudo M, Kudo T, Smart D, Matsuki A (2003) Effects of central hypocretin-1 administration on hemodynamic responses in young-adult and middle-aged rats. Brain Res 981(1–2):143–150PubMedGoogle Scholar
  82. 82.
    Samson WK, Bagley SL, Ferguson AV, White MM (2007) Hypocretin/orexin type 1 receptor in brain: role in cardiovascular control and the neuroendocrine response to immobilization stress. Am J Physiol 292(1):R382–R387. doi: 10.1152/ajpregu.00496.2006CrossRefGoogle Scholar
  83. 83.
    Huang S-C, Dai Y-WE, Lee Y-H, Chiou L-C, Hwang L-L (2010) Orexins depolarize rostral ventrolateral medulla neurons and increase arterial pressure and heart rate in rats mainly via orexin 2 receptors. J Pharmacol Exp Ther 334(2):522–529. doi: 10.1124/jpet.110.167791CrossRefPubMedGoogle Scholar
  84. 84.
    Antunes VR, Brailoiu GC, Kwok EH, Scruggs P, Dun NJ (2001) Orexins/hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro. Am J Physiol 281(6):R1801–R1807Google Scholar
  85. 85.
    Zhang W, Fukuda Y, Kuwaki T (2005) Respiratory and cardiovascular actions of orexin-A in mice. Neurosci Lett 385(2):131–136PubMedGoogle Scholar
  86. 86.
    Machado BH, Bonagamba LGH, Dun SL, Kwok EH, Dun NJ (2002) Pressor response to microinjection of orexin/hypocretin into rostral ventrolateral medulla of awake rats. Regul Pept 104:75–81PubMedGoogle Scholar
  87. 87.
    Dun NJ, Le Dun S, Chen CT, Hwang LL, Kwok EH, Chang JK (2000) Orexins: a role in medullary sympathetic outflow. Regul Pept. 96(1–2):65–70PubMedGoogle Scholar
  88. 88.
    Xiao F, Jiang M, Du D, Xia C, Wang J, Cao Y, Shen L, Zhu D (2012) Orexin A regulates cardiovascular responses in stress-induced hypertensive rats. Neuropharmacology 67C:16–24. doi: 10.1016/j.neuropharm.2012.10.021CrossRefGoogle Scholar
  89. 89.
    Luong LNL, Carrive P (2012) Orexin microinjection in the medullary raphé increases heart rate and arterial pressure but does not reduce tail skin blood flow in the awake rat. Neuroscience 202:209–217. doi: 10.1016/j.neuroscience.2011.11.073CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Ciriello J, Caverson MM, McMurray JC, Bruckschwaiger EB (2013) Co-localization of hypocretin-1 and leucine-enkephalin in hypothalamic neurons projecting to the nucleus of the solitary tract and their effect on arterial pressure. Neuroscience 250:599–613. doi: 10.1016/j.neuroscience.2013.07.054CrossRefPubMedGoogle Scholar
  91. 91.
    Shih C-D, Chuang Y-C (2007) Nitric oxide and GABA mediate bi-directional cardiovascular effects of orexin in the nucleus tractus solitarii of rats. Neuroscience 149(3):625–635. doi: 10.1016/j.neuroscience.2007.07.016CrossRefPubMedGoogle Scholar
  92. 92.
    Smith PM, Samson WK, Ferguson AV (2007) Cardiovascular actions of orexin-A in the rat subfornical organ. J Neuroendocrinol. 19(1):7–13PubMedGoogle Scholar
  93. 93.
    Iigaya K, Horiuchi J, McDowall LM, Lam ACB, Sediqi Y, Polson JW, Carrive P, Dampney RAL (2012) Blockade of orexin receptors with Almorexant reduces cardiorespiratory responses evoked from the hypothalamus but not baro- or chemoreceptor reflex responses. Am J Physiol 303(10):R1011–R1022. doi: 10.1152/ajpregu.00263.2012CrossRefGoogle Scholar
  94. 94.
    Stettner GM, Kubin L (2013) Antagonism of orexin receptors in the posterior hypothalamus reduces hypoglossal and cardiorespiratory excitation from the perifornical hypothalamus. J Appl Physiol 114(1):119–130. doi: 10.1152/japplphysiol.00965.2012CrossRefPubMedGoogle Scholar
  95. 95.
    Beig MI, Dampney BW, Carrive P (2014) Both Ox1r and Ox2r orexin receptors contribute to the cardiovascular and locomotor components of the novelty stress response in the rat. Neuropharmacology 89C:146–156. doi: 10.1016/j.neuropharm.2014.09.012CrossRefGoogle Scholar
  96. 96.
    Nisimaru N, Mittal C, Shirai Y, Sooksawate T, Anandaraj P, Hashikawa T, Nagao S, Arata A, Sakurai T, Yamamoto M, Ito M (2013) Orexin-neuromodulated cerebellar circuit controls redistribution of arterial blood flows for defense behavior in rabbits. Proc Natl Acad Sci U S A. doi: 10.1073/pnas.1312804110CrossRefPubMedPubMedCentralGoogle Scholar
  97. 97.
    Rusyniak DE, Zaretsky DV, Zaretskaia MV, Dimicco JA (2011) The role of orexin-1 receptors in physiologic responses evoked by microinjection of PgE2 or muscimol into the medial preoptic area. Neurosci Lett 498(2):162–166. doi: 10.1016/j.neulet.2011.05.006CrossRefPubMedPubMedCentralGoogle Scholar
  98. 98.
    Furlong TM, Vianna DML, Liu L, Carrive P (2009) Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal. Europ J Neurosci 30(8):1603–1614. doi: 10.1111/j.1460-9568.2009.06952.xCrossRefGoogle Scholar
  99. 99.
    Johnson PL, Truitt W, Fitz SD, Minick PE, Dietrich A, Sanghani S, Träskman-Bendz L, Goddard AW, Brundin L, Shekhar A (2009) A key role for orexin in panic anxiety. Nat Med 16(1):111–115. doi: 10.1038/nm.2075CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Johnson PL, Federici LM, Fitz SD, Renger JJ, Shireman B, Winrow CJ, Bonaventure P, Shekhar A (2015) Orexin 1 and 2 receptor involvement in co2 -induced panic-associated behavior and autonomic responses. Depress Anxiety 32(9):671–683. doi: 10.1002/da.22403CrossRefPubMedPubMedCentralGoogle Scholar
  101. 101.
    Johnson PL, Samuels BC, Fitz SD, Federici LM, Hammes N, Early MC, Truitt W, Lowry CA, Shekhar A (2012) Orexin 1 receptors are a novel target to modulate panic responses and the panic brain network. Physiol Behav 107(5):733–742. doi: 10.1016/j.physbeh.2012.04.016CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Rusyniak DE, Zaretsky DV, Zaretskaia MV, Durant PJ, Dimicco JA (2012) The orexin-1 receptor antagonist SB-334867 decreases sympathetic responses to a moderate dose of methamphetamine and stress. Physiol Behav 107(5):743–750. doi: 10.1016/j.physbeh.2012.02.010CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Allard JS, Tizabi Y, Shaffery JP, Manaye K (2007) Effects of rapid eye movement sleep deprivation on hypocretin neurons in the hypothalamus of a rat model of depression. Neuropeptides 41(5):329–337PubMedPubMedCentralGoogle Scholar
  104. 104.
    Chen X, Li S, Kirouac GJ (2014) Blocking of corticotrophin releasing factor receptor-1 during footshock attenuates context fear but not the upregulation of prepro-orexin mRNA in rats. Pharmacol Biochem Behav 120:1–6. doi: 10.1016/j.pbb.2014.01.013CrossRefPubMedGoogle Scholar
  105. 105.
    Chen X, Wang H, Lin Z, Li S, Li Y, Bergen HT, Vrontakis ME, Kirouac GJ (2013) Orexins (hypocretins) contribute to fear and avoidance in rats exposed to a single episode of footshocks. Brain Struct Funct. doi: 10.1007/s00429-013-0626-3CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    Hayward LF, Hampton EE, Ferreira LF, Christou DD, Yoo J-K, Hernandez ME, Martin EJ (2015) Chronic heart failure alters orexin and melanin concentrating hormone but not corticotrophin releasing hormone-related gene expression in the brain of male Lewis rats. Neuropeptides. doi: 10.1016/j.npep.2015.06.001CrossRefPubMedGoogle Scholar
  107. 107.
    Frey A, Popp S, Post A, Langer S, Lehmann M, Hofmann U, Sirén A-L, Hommers L, Schmitt A, Strekalova T, Ertl G, Lesch K-P, Frantz S (2014) Experimental heart failure causes depression-like behavior together with differential regulation of inflammatory and structural genes in the brain. Front Behav Neurosci 8:376. doi: 10.3389/fnbeh.2014.00376CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Schoemaker RG, Smits JF (1994) Behavioral changes following chronic myocardial infarction in rats. Physiol Behav 56(3):585–589PubMedGoogle Scholar
  109. 109.
    Carretero OA, Oparil S (2000) Essential hypertension. Part I: definition and etiology. Circulation 101(3):329–335PubMedGoogle Scholar
  110. 110.
    Fisher JP, Paton JFR (2012) The sympathetic nervous system and blood pressure in humans: implications for hypertension. J Hum Hypertens 26(8):463–475. doi: 10.1038/jhh.2011.66CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Korner P (2007) Essential hypertension and its causes: neural and non-neural mechanisms. Oxford University Press, New YorkGoogle Scholar
  112. 112.
    Lee Y-H, Dai Y-WE, Huang S-C, Li TL, Hwang L-L (2013) Blockade of central orexin 2 receptors reduces arterial pressure in spontaneously hypertensive rats. Exp Physiol. doi: 10.1113/expphysiol.2013.072298CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Li A, Hindmarch CCT, Nattie EE, Paton JFR (2013) Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats. J Physiol. doi: 10.1113/jphysiol.2013.256271CrossRefPubMedPubMedCentralGoogle Scholar
  114. 114.
    Clifford L, Dampney BW, Carrive P (2015) Spontaneously hypertensive rats have more orexin neurons in their medial hypothalamus than normotensive rats. Exp Physiol 100(4):388–398. doi: 10.1113/expphysiol.2014.084137CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Lee Y-H, Tsai M-C, Li TL, Dai Y-WE, Huang S-C, Hwang L-L (2015) Spontaneously hypertensive rats have more orexin neurons in the hypothalamus and enhanced orexinergic input and orexin 2 receptor-associated nitric oxide signalling in the rostral ventrolateral medulla. Exp Physiol. doi: 10.1113/EP085016CrossRefPubMedGoogle Scholar
  116. 116.
    Paré WP (1989) Stress ulcer and open-field behavior of spontaneously hypertensive, normotensive, and Wistar rats. Pavlov J Biol Sci 24(2):54–57PubMedGoogle Scholar
  117. 117.
    Sagvolden T (2000) Behavioral validation of the spontaneously hypertensive rat (SHR) as an animal model of attention-deficit/hyperactivity disorder (AD/HD). Neurosci Biobehav Rev 24(1):31–39PubMedGoogle Scholar
  118. 118.
    Sagvolden T, Pettersen MB, Larsen MC (1993) Spontaneously hypertensive rats (SHR) as a putative animal model of childhood hyperkinesis: SHR behavior compared to four other rat strains. Physiol Behav 54(6):1047–1055PubMedGoogle Scholar
  119. 119.
    Davern PJ, Nguyen-Huu T-P, La Greca L, Abdelkader A, Head GA (2009) Role of the sympathetic nervous system in Schlager genetically hypertensive mice. Hypertension 54(4):852–859. doi: 10.1161/HYPERTENSIONAHA.109.136069CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Schlager G (1974) Selection for blood pressure levels in mice. Genetics 76(3):537–549PubMedPubMedCentralGoogle Scholar
  121. 121.
    Marques FZ, Campain AE, Davern PJ, Yang YHJ, Head GA, Morris BJ (2011) Genes influencing circadian differences in blood pressure in hypertensive mice. PLoS One 6 (4):e19203. doi: 10.1371/journal.pone.0019203PubMedPubMedCentralGoogle Scholar
  122. 122.
    Marques FZ, Campain AE, Davern PJ, Yang YHJ, Head GA, Morris BJ (2011) Global identification of the genes and pathways differentially expressed in hypothalamus in early and established neurogenic hypertension. Physiol Genomics 43 (12):766–771. doi: 10.1152/physiolgenomics.00009.2011PubMedGoogle Scholar
  123. 123.
    Jackson KL, Dampney BW, Moretti J-L, Stevenson ER, Davern PJ, Carrive P, Head GA (2016) The contribution of orexin to the neurogenic hypertension in BPH/2 J mice. Hypertension 67(5):959–969PubMedGoogle Scholar
  124. 124.
    Deng B-S, Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T (2007) Contribution of orexin in hypercapnic chemoreflex: evidence from genetic and pharmacological disruption and supplementation studies in mice. J Appl Physiol 103(5):1772–1779PubMedGoogle Scholar
  125. 125.
    Sugita T, Sakuraba S, Kaku Y, Yoshida K, Arisakaa H, Kuwana S (2014) Orexin induces excitation of respiratory neuronal network in isolatedbrainstem spinal cord of neonatal rat. Respir Physiol Neurobiol 200:105–109PubMedGoogle Scholar
  126. 126.
    Dutschmann M, Kron M, Mörschel M, Gestreau C (2007) Activation of Orexin B receptors in the pontine Kölliker-Fuse nucleus modulates pre-inspiratory hypoglossal motor activity in rat. Respir Physiol Neurobiol 159(2):232–235PubMedGoogle Scholar
  127. 127.
    Peever JH, Lai Y-Y, Siegel JM (2003) Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are reversed by NMDA antagonism. J Neurophysiol 89:2591–2600PubMedGoogle Scholar
  128. 128.
    Zhang GH, Liu ZL, Zhang BJ, Geng WY, Song NN, Zhou W, Cao YX, Li SQ, Huang ZL, Shen LL (2014) Orexin A activates hypoglossal motoneurons and enhances genioglossus muscle activity in rats. Br J Pharmacol 171:4233–4246PubMedPubMedCentralGoogle Scholar
  129. 129.
    Krieger J (2000) Respiratory physiology: breathing in normal subjects. In: Kryger MH, Roth T, Dement WC (eds) Principles and practice of sleep medicine. W.B. Saunders, Philadelphia, pp. 229–241Google Scholar
  130. 130.
    Douglas NJ (2000) Respiratory physiology: control of ventilation. In: Kryger MH, Roth T, Dement WC (eds) Principles and practice of sleep medicine. W.B. Saunders, Philadelphia, pp. 221–228Google Scholar
  131. 131.
    Lee M, Hassani O, Jones B (2005) Discharge of identified orexin/hypocretin neurons across the sleep-waking cycle. J Neurosci 25(28):6716–6720PubMedPubMedCentralGoogle Scholar
  132. 132.
    Mileykovskiy B, Kiyashchenko L, Siegel J (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46(5):787–798PubMedPubMedCentralGoogle Scholar
  133. 133.
    Takahashi K, Lin JS, Sakai K (2008) Neuronal activity of orexin and non-orexin waking-active neurons during wake–sleep states in the mouse. Neuroscience 153:860–870PubMedPubMedCentralGoogle Scholar
  134. 134.
    Kuwaki T (2015) Thermoregulation under pressure: a role for orexin neurons. Temperature 2:379–391Google Scholar
  135. 135.
    Espana RA, Valentino RJ, Berridge CW (2003) Fos immunoreactivity in hypocretin-synthesizing and hypocretin-1 receptor-expressing neurons: effects of diurnal and nocturnal spontaneous waking, stress and hypocretin-1 administration. Neuroscience 121(1):201–217PubMedGoogle Scholar
  136. 136.
    Ida T, Nakahara K, Murakami T, Hanada R, Nakazato M, Murakami N (2000) Possible involvement of orexin in the stress reaction in rats. Biochem Biophys Res Commun 270(1):318–323PubMedGoogle Scholar
  137. 137.
    Kuwaki T, Zhang W, Nakamura A (2007) State-dependent adjustment of the central autonomic regulation: role of orexin in emotional behavior and sleep/wake cycle. In: Kubo T, Kuwaki T (eds) Central mechanisms of cardiovascular regulation. Research Signport, Kerala, India, pp. 57–73Google Scholar
  138. 138.
    Watanabe S, Kuwaki T, Yanagisawa M, Fukuda Y, Shimoyama M (2005) Persistent pain and stress activate pain-inhibitory orexin pathways. Neuroreport 16(1):5–8PubMedGoogle Scholar
  139. 139.
    Winsky-Sommerer R, Yamanaka A, Diano S, Borok E, Roberts AJ, Sakurai T, Kilduff TS, Horvath TL, de Lecea L (2004) Interaction between the corticotropin-releasing factor system and hypocretins (orexins): a novel circuit mediating stress response. J Neurosci 24(50):11439–11448Google Scholar
  140. 140.
    Zhang W, Sunanaga J, Takahashi Y, Mori T, Sakurai T, Kanmura Y, Kuwaki T (2010) Orexin neurons are indispensable for stress-induced thermogenesis in mice. J Physiol 588(21):4117–4129PubMedPubMedCentralGoogle Scholar
  141. 141.
    Zhu L, Onaka T, Sakurai T, Yada T (2002) Activation of orexin neurones after noxious but not conditioned fear stimuli in rats. Neuroreport 13(10):1351–1353PubMedGoogle Scholar
  142. 142.
    Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, Kuwaki T (2007) Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 102:241–248PubMedGoogle Scholar
  143. 143.
    Kuwaki T, Deng B-S, Nakamura A, Zhang W, Yanagisawa M, Fukuda Y (2005) Abnormal respiration in orexin knockout mice. In: Kumar A, Mallick H (eds) Proceedings of the 2nd interim congress of the world federation of sleep research and sleep medicine society. Medimond S.r.l, Bologna, Italy, pp. 69–72Google Scholar
  144. 144.
    Kuwaki T (2008) Orexinergic modulation of breathing across vigilance states. Respir Physiol Neurobiol 164:204–212PubMedGoogle Scholar
  145. 145.
    Williams RH, Jensen LT, Verkhratsky A, Fugger L, Burdakov D (2007) Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci U S A 104(25):10685–10690PubMedPubMedCentralGoogle Scholar
  146. 146.
    Sunanaga J, Deng B-S, Zhang W, Kanmura Y, Kuwaki T (2009) CO2 activates orexin-containing neurons in mice. Respir Physiol Neurobiol 166(3):184–186PubMedGoogle Scholar
  147. 147.
    Phillipson E (1978) Control of breathing during sleep. Am Rev Respir Dis 118:909–939PubMedGoogle Scholar
  148. 148.
    Dias MB, Li A, Nattie EE (2010) The orexin receptor-1 (OX1R) in the rostral medullary raphé contributes to the hypercapnic chemoreflex in wakefulness, during the active period of the diurnal cycle. Respir Physiol Neurobiol 170(9):96–102PubMedGoogle Scholar
  149. 149.
    Dias M, Li A, Nattie E (2009) Antagonism of orexin receptor-1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness. J Physiol 587(9):2059–2067PubMedPubMedCentralGoogle Scholar
  150. 150.
    Kuwaki T, Li A, Nattie EE (2010) State-dependent central chemoreception: a role of orexin. Respir Physiol Neurobiol 173:223–229PubMedPubMedCentralGoogle Scholar
  151. 151.
    Han F, Mignot E, Wei Y, Dong S, Li J, Lin L, An P, Wang L, Wang J, He M, Gao H, Li M, Gao Z, Strohl K (2010) Ventilatory chemoresponsiveness, narcolepsy-cataplexy and human leukocyte antigen DQB1*0602 status. Eur Respir J 36(3):577–583PubMedGoogle Scholar
  152. 152.
    Nakamura A, Fukuda Y, Kuwaki T (2003) Sleep apnea and effect of chemostimulation on breathing instability in mice. J Appl Physiol 94(2):525–532PubMedGoogle Scholar
  153. 153.
    Nakamura A, Kuwaki T (2004) Sleep apnea in mice: a useful animal model for study of SIDS? Pathophysiology 10(3/4):253–257Google Scholar
  154. 154.
    Moore MW, Akladious A, Hu Y, Azzam S, Feng P, Strohl KP (2014) Effects of orexin 2 receptor activation on apnea in the C57BL/6 J mouse. Respir Physiol Neurobiol 200:118–125PubMedPubMedCentralGoogle Scholar
  155. 155.
    Tarasiuk A, Levi A, Berdugo-Boura N, Yahalom A, Segev Y (2014) Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats. Sleep 37:987–998PubMedPubMedCentralGoogle Scholar
  156. 156.
    Chokroverty S (1986) Sleep apnea in narcolepsy. Sleep 9:250–253PubMedGoogle Scholar
  157. 157.
    Harsh J, Peszka J, Hartwig G, Mitler M (2000) Night-time sleep and daytime sleepiness in narcolepsy. J Sleep Res 9:309–316PubMedGoogle Scholar
  158. 158.
    Yamaguchi K, Futatsuki T, Ushikai J, Kuroki C, Minami T, Kakihana Y, Kuwaki T (2015) Intermittent but not sustained hypoxia activates orexin-containing neurons in mice. Respir Physiol Neurobiol 206:11–14PubMedGoogle Scholar
  159. 159.
    Terada J, Nakamura A, Zhang W, Yanagisawa M, Kuriyama T, Fukuda Y, Kuwaki T (2008) Ventilatory long-term facilitation in mice can be observed both during sleep and wake periods and depends on orexin. J Appl Physiol 104(2):499–507PubMedGoogle Scholar
  160. 160.
    Toyama S, Sakurai T, Tatsumi K, Kuwaki T (2009) Attenuated phrenic long-term facilitation in orexin neuron-ablated mice. Respir Physiol Neurobiol 168(3):295–302PubMedGoogle Scholar
  161. 161.
    Cai XJ, Evans ML, Lister CA, Leslie RA, Arch JRS, Wilson S, Williams G (2001) 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 50:105–112PubMedGoogle Scholar
  162. 162.
    Burdakov D, Gerasimenko O, Verkhratsky A (2005) Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ. J Neurosci 25(9):2429–2433PubMedGoogle Scholar
  163. 163.
    Burdakov D, Jensen LT, Alexopoulos H, Williams RH, Fearon IM, O’Kelly I, Gerasimenko O, Fugger L, Verkhratsky A (2006) Tandem-pore K+ channels mediate inhibition of orexin neurons by glucose. Neuron 50(5):711–722PubMedGoogle Scholar
  164. 164.
    Polotsky VY, Wilson JA, Haines AS, Scharf MT, Soutiere SE, Tankersley CG, Smith PL, Schwartz AR, O’Donnell CP (2001) The impact of insulin-dependent diabetes on ventilatory control in the mouse. Am J Respir Crit Care Med 163:624–632PubMedGoogle Scholar
  165. 165.
    Punjabi NM, Shahar E, Rediline S, Gottlieb DJ, Givelber R, Resnick HE, Sleep Heat Health Study Investigators (2004) Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. Am J Epidemiol 160:521–530PubMedGoogle Scholar
  166. 166.
    Jordan AS, White DP (2008) Pharyngeal motor control and the pathogenesis of obstructive sleep apnea. Respir Physiol Neurobiol 160(1):1–7PubMedGoogle Scholar
  167. 167.
    Sakurai S, Nishijima T, Takahashi S, Yamauchi K, Arihara Z, Takahashi K (2005) Low plasma orexin-A levels were improved by continuous positive airway pressure treatment in patients with severe obstructive sleep apnea-hypopnea syndrome. Chest 127(3):731–737PubMedGoogle Scholar
  168. 168.
    Busquets X, Barbe F, Barcelo A, de la Pena M, Sigritz N, Mayoralas L, Ladaria A, Agusti A (2004) Decreased plasma levels of orexin-A in sleep apnea. Respiration 71(6):575–579PubMedGoogle Scholar
  169. 169.
    Igarashi N, Tatsumi K, Nakamura A, Sakao S, Takiguchi Y, Nishikawa T, Kuriyama T (2003) Plasma orexin-A levels in obstructive sleep apnea-hypopnea syndrome. Chest 124(4):1381–1385PubMedGoogle Scholar
  170. 170.
    Kanbayashi T, Inoue Y, Kawanishi K, Takasaki H, Aizawa R, Takahashi K, Ogawa Y, Abe M, Hishikawa Y, Shimizu T (2003) CSF hypocretin measures in patients with obstructive sleep apnea. J Sleep Res 12(4):339–341PubMedGoogle Scholar
  171. 171.
    Sun H, Palcza J, Rosenberg R, Kryger M, Siringhaus T, Rowe J, Lines C, Wagner JA, Troyer MD (2015) Effects of suvorexant, an orexin receptor antagonist, on breathing during sleep in patients with chronic obstructive pulmonary disease. Resp Med 109:416–426Google Scholar

Copyright information

© Springer International Publishing AG 2016

Open Access This chapter is licensed under the terms of the Creative Commons Attribution-NonCommercial 2.5 International License (http://creativecommons.org/licenses/by-nc/2.5/), which permits any noncommercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license and indicate if changes were made.

The images or other third party material in this chapter are included in the chapter's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the chapter's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

Authors and Affiliations

  1. 1.School of Medical SciencesUniversity of New South WalesSydneyAustralia
  2. 2.Department of Physiology, Graduate School of Medical & Dental SciencesKagoshima UniversityKagoshimaJapan

Personalised recommendations