Orexin and Central Modulation of Cardiovascular and Respiratory Function

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.1202526109 PubMedPubMedCentralCrossRefGoogle 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/nature04284 PubMedCrossRefGoogle 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.3810 PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Sakurai T (2014) The role of orexin in motivated behaviours. Nat Rev Neurosci 15(11):719–731. doi: 10.1038/nrn3837 PubMedCrossRefGoogle 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):243–260PubMedCrossRefGoogle 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):9996–10015PubMedGoogle 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) 154:491–513CrossRefGoogle Scholar
  8. 8.
    Hilton SM (1982) The defence-arousal system and its relevance for circulatory and respiratory control. J Exp Biol 100:159–174PubMedGoogle 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.00671.2002 Google 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–R954PubMedCrossRefGoogle 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. 220–237CrossRefGoogle 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.10860 PubMedCrossRefGoogle 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–E1655PubMedPubMedCentralCrossRefGoogle 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):322–327PubMedPubMedCentralCrossRefGoogle 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.2009.10.061 PubMedCrossRefGoogle 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.2005.03.010 PubMedCrossRefGoogle 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.20859 PubMedPubMedCentralCrossRefGoogle 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):517–523PubMedCrossRefGoogle Scholar
  20. 20.
    Saper CB (2004) Central autonomic nervous system. In: Paxinos G (ed) The rat nervous system, 3rd edn. Elsevier, San Diego, pp. 761–794CrossRefGoogle 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.23643 PubMedPubMedCentralCrossRefGoogle 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):616–629PubMedCrossRefGoogle 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):701–713PubMedCrossRefGoogle 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.10783 PubMedCrossRefGoogle 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-x PubMedCrossRefGoogle 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.00719.2002 Google 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):84–95PubMedCrossRefGoogle Scholar
  28. 28.
    Geerling JC, Mettenleiter TC, Loewy AD (2003) Orexin neurons project to diverse sympathetic outflow systems. Neuroscience 122(2):541–550PubMedCrossRefGoogle 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.2010.12.003 PubMedCrossRefGoogle 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.22603 PubMedCrossRefGoogle 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.2010.04.020 PubMedCrossRefGoogle 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.21105 PubMedCrossRefGoogle 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.x PubMedPubMedCentralCrossRefGoogle 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):707–714PubMedCrossRefGoogle 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.3909-11.2011 PubMedPubMedCentralCrossRefGoogle 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.00914.2004 PubMedCrossRefGoogle 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):205–217PubMedCrossRefGoogle 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.20515 PubMedCrossRefGoogle 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):87–90PubMedCrossRefGoogle 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):115–119PubMedCrossRefGoogle 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):257–262PubMedCrossRefGoogle Scholar
  43. 43.
    Volgin DV, Saghir M, Kubin L (2002) Developmental changes in the orexin 2 receptor mRNA in hypoglossal motoneurons. Neuroreport 13(4):433–436PubMedCrossRefGoogle 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.00877.2002 Google 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 161:20–27CrossRefGoogle 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.111.005546 PubMedCrossRefGoogle Scholar
  48. 48.
    Leonard CS, Kukkonen JP (2014) Orexin/hypocretin receptor signalling: a functional perspective. Br J Pharmacol 171:294–313PubMedCrossRefGoogle 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.2014.00057 PubMedPubMedCentralGoogle 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.2000.1584 PubMedCrossRefGoogle 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):6–25PubMedCrossRefGoogle 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):27–34PubMedCrossRefGoogle 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):71–75PubMedCrossRefGoogle 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.2002.033290 PubMedPubMedCentralGoogle 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):131–144PubMedCrossRefGoogle 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):176–182PubMedCrossRefGoogle 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):777–797PubMedCrossRefGoogle 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):315–328CrossRefGoogle 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.2120-10.2010 PubMedCrossRefGoogle 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: 10.1111/1440-1681.12461 PubMedCrossRefGoogle 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.2015.06.011 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Kukkonen JP (2012) Recent progress in orexin/hypocretin physiology and pharmacology. Biomol Concepts 3:447–463PubMedCrossRefGoogle 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.2015.03.002 PubMedGoogle 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.2014.08.027 PubMedCrossRefGoogle 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.0039131 PubMedPubMedCentralCrossRefGoogle 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-010510-100528 PubMedPubMedCentralCrossRefGoogle 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.201300003 PubMedCrossRefGoogle 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.114.220392 PubMedPubMedCentralCrossRefGoogle 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.2012.08.109 PubMedCrossRefGoogle 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):4497–4499CrossRefGoogle 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.x PubMedPubMedCentralCrossRefGoogle 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/nm1544 PubMedCrossRefGoogle 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.109.055152 PubMedCrossRefGoogle 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):111–113PubMedCrossRefGoogle 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):213–218PubMedPubMedCentralCrossRefGoogle 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.00704.2005 Google 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):248–253PubMedCrossRefGoogle 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.x PubMedPubMedCentralCrossRefGoogle 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):143–150PubMedCrossRefGoogle 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.00496.2006 Google 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.110.167791 PubMedCrossRefGoogle 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):131–136PubMedCrossRefGoogle 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 104:75–81PubMedCrossRefGoogle 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):65–70PubMedCrossRefGoogle 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.2012.10.021 Google 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.2011.11.073 PubMedCrossRefGoogle 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.2013.07.054 PubMedCrossRefGoogle 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.2007.07.016 PubMedCrossRefGoogle Scholar
  92. 92.
    Smith PM, Samson WK, Ferguson AV (2007) Cardiovascular actions of orexin-A in the rat subfornical organ. J Neuroendocrinol. 19(1):7–13PubMedCrossRefGoogle 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.00263.2012 Google 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.00965.2012 PubMedCrossRefGoogle 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.2014.09.012 Google 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.1312804110 PubMedPubMedCentralGoogle 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.2011.05.006 PubMedPubMedCentralCrossRefGoogle 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.x CrossRefGoogle 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.2075 PubMedPubMedCentralCrossRefGoogle 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.22403 PubMedPubMedCentralCrossRefGoogle 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.2012.04.016 PubMedPubMedCentralCrossRefGoogle 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.2012.02.010 PubMedPubMedCentralCrossRefGoogle 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):329–337PubMedPubMedCentralCrossRefGoogle 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.2014.01.013 PubMedCrossRefGoogle 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/s00429-013-0626-3 Google 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.2015.06.001 PubMedGoogle 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.2014.00376 PubMedPubMedCentralCrossRefGoogle Scholar
  108. 108.
    Schoemaker RG, Smits JF (1994) Behavioral changes following chronic myocardial infarction in rats. Physiol Behav 56(3):585–589PubMedCrossRefGoogle Scholar
  109. 109.
    Carretero OA, Oparil S (2000) Essential hypertension. Part I: definition and etiology. Circulation 101(3):329–335PubMedCrossRefGoogle 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.2011.66 PubMedCrossRefGoogle 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.2013.072298 PubMedCentralGoogle 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.2013.256271 Google 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.2014.084137 PubMedCrossRefGoogle 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/EP085016 PubMedGoogle 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):31–39PubMedCrossRefGoogle 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):1047–1055PubMedCrossRefGoogle 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.109.136069 PubMedCrossRefGoogle 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.0019203
  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.00009.2011
  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):959–969PubMedCrossRefGoogle 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):1772–1779PubMedCrossRefGoogle 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 200:105–109PubMedCrossRefGoogle 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):232–235PubMedCrossRefGoogle 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 89:2591–2600PubMedCrossRefGoogle 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 171:4233–4246PubMedPubMedCentralCrossRefGoogle 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):6716–6720PubMedCrossRefGoogle Scholar
  132. 132.
    Mileykovskiy B, Kiyashchenko L, Siegel J (2005) Behavioral correlates of activity in identified hypocretin/orexin neurons. Neuron 46(5):787–798PubMedCrossRefGoogle 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 153:860–870PubMedCrossRefGoogle Scholar
  134. 134.
    Kuwaki T (2015) Thermoregulation under pressure: a role for orexin neurons. Temperature 2:379–391CrossRefGoogle 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):201–217PubMedCrossRefGoogle 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):318–323PubMedCrossRefGoogle 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):5–8PubMedCrossRefGoogle 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):11439–11448PubMedCrossRefGoogle 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):4117–4129PubMedPubMedCentralCrossRefGoogle 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):1351–1353PubMedCrossRefGoogle 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 102:241–248PubMedCrossRefGoogle 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 164:204–212PubMedCrossRefGoogle 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):10685–10690PubMedPubMedCentralCrossRefGoogle 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):184–186PubMedCrossRefGoogle 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):96–102PubMedCrossRefGoogle 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):2059–2067PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Kuwaki T, Li A, Nattie EE (2010) State-dependent central chemoreception: a role of orexin. Respir Physiol Neurobiol 173:223–229PubMedPubMedCentralCrossRefGoogle 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):577–583PubMedCrossRefGoogle 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):525–532PubMedCrossRefGoogle Scholar
  153. 153.
    Nakamura A, Kuwaki T (2004) Sleep apnea in mice: a useful animal model for study of SIDS? Pathophysiology 10(3/4):253–257CrossRefGoogle 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 200:118–125PubMedPubMedCentralCrossRefGoogle 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 37:987–998PubMedPubMedCentralCrossRefGoogle Scholar
  156. 156.
    Chokroverty S (1986) Sleep apnea in narcolepsy. Sleep 9:250–253PubMedCrossRefGoogle Scholar
  157. 157.
    Harsh J, Peszka J, Hartwig G, Mitler M (2000) Night-time sleep and daytime sleepiness in narcolepsy. J Sleep Res 9:309–316PubMedCrossRefGoogle 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 206:11–14PubMedCrossRefGoogle 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):499–507PubMedCrossRefGoogle 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):295–302PubMedCrossRefGoogle 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 50:105–112PubMedCrossRefGoogle 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):2429–2433PubMedCrossRefGoogle 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):711–722PubMedCrossRefGoogle 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 163:624–632PubMedCrossRefGoogle 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 160:521–530PubMedCrossRefGoogle Scholar
  166. 166.
    Jordan AS, White DP (2008) Pharyngeal motor control and the pathogenesis of obstructive sleep apnea. Respir Physiol Neurobiol 160(1):1–7PubMedCrossRefGoogle 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):731–737PubMedCrossRefGoogle 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):575–579PubMedCrossRefGoogle 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):1381–1385PubMedCrossRefGoogle 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):339–341PubMedCrossRefGoogle 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 109:416–426CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2016

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

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