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Orexinergic Tone in Cardiorespiratory Regulation

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Orexin and Sleep

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Abstract

Orexin-containing cells are located in the posterior lateral hypothalamus and send axonal projections to all brain and spinal cord locations important for the control of sleep-wake states, breathing, blood pressure, heart rate and motor activity, as well as mood, attention and motivation. While their strategic location and widespread efferent connections suggest that orexin neurons have major and multifaceted roles, elimination of orexins or their receptors results in a relatively discrete and focused deficiency—narcolepsy/cataplexy. Orexin-deficient rodents have been relatively extensively used to assess the role of endogenous orexins in cardiorespiratory regulation. Orexin receptor antagonists have been developed with a delay after the discovery of orexins and their use for focal probing of the endogenous role of orexins in different brain regions has been limited. Despite intense research, it is still unclear under which conditions orexins are physiologically important for the many different roles ascribed to them based on their anatomical connectivity and effects of focal administration of synthetic orexins. Here, we review recent studies which aimed to elucidate the endogenous role of orexins in the control of breathing and blood pressure under different physiologic and pathophysiologic conditions.

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References

  • Ahmed WA, Tsutsumi M, Nakata S et al (2012) A functional variation in the hypocretin neuropeptide precursor gene may be associated with obstructive sleep apnea syndrome in Japan. Laryngoscope 122:925–929

    Article  CAS  PubMed  Google Scholar 

  • Antunes VR, Brailoiu GC, Kwok EH et al (2001) Orexins/hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro. Am J Physiol 281:R1801–R1807

    CAS  Google Scholar 

  • Aserinsky E, Kleitman N (1953) Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 118:273–274

    Article  CAS  PubMed  Google Scholar 

  • Bastianini S, Silvani A, Berteotti C et al (2011) Sleep related changes in blood pressure in hypocretin-deficient narcoleptic mice. Sleep 34:213–218

    PubMed Central  PubMed  Google Scholar 

  • Betschart C, Hintermann S, Behnke D et al (2013) Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia. J Med Chem 56:7590–7607

    Article  CAS  PubMed  Google Scholar 

  • Bourgin P, HuitrĂłn-ResĂ©ndiz S, Spier AD et al (2000) Hypocretin-1 modulates rapid eye movement sleep through activation of locus coeruleus neurons. J Neurosci 20:7760–7765

    CAS  PubMed  Google Scholar 

  • Brisbare-Roch C, Dingemanse J, Koberstein R et al (2007) Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 13:150–155

    Article  CAS  PubMed  Google Scholar 

  • Busquets X, BarbĂ© F, BarcelĂł A et al (2004) Decreased plasma levels of orexin-A in sleep apnea. Respiration 71:575–579

    Article  CAS  PubMed  Google Scholar 

  • Cerri M, Morrison SF (2005) Activation of lateral hypothalamic neurons stimulates brown adipose tissue thermogenesis. Neuroscience 135:627–638

    Article  CAS  PubMed  Google Scholar 

  • Chan E, Steenland HW, Liu H, Horner RL (2006) Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states. Am J Respir Crit Care Med 174:1264–1273

    Article  CAS  PubMed  Google Scholar 

  • Chemelli RM, Willie JT, Sinton CM et al (1999) Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell 98:437–451

    Article  CAS  PubMed  Google Scholar 

  • Chen W, Ye J, Han D et al (2012) Association of prepro-orexin polymorphism with obstructive sleep apnea/hypopnea syndrome. Am J Otolaryngol 33:31–36

    Article  PubMed  Google Scholar 

  • Corcoran A, Richerson G, Harris M (2010) Modulation of respiratory activity by hypocretin-1 (orexin A) in situ and in vitro. Adv Exp Med Biol 669:109–113

    Article  CAS  PubMed  Google Scholar 

  • Date Y, Ueta Y, Yamashita H et al (1999) Orexins, orexigenic hypothalamic peptides, interact with autonomic, neuroendocrine and neuroregulatory systems. Proc Natl Acad Sci USA 96:748–753

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • de Lecea L, Kilduff TS, Peyron C et al (1998) The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc Natl Acad Sci USA 95:322–327

    Article  PubMed Central  PubMed  Google Scholar 

  • Dias MB, Li A, Nattie EE (2009) Antagonism of orexin receptor-1 in the retrotrapezoid nucleus inhibits the ventilatory response to hypercapnia predominantly in wakefulness. J Physiol 587:2059–2067

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • DiMicco JA, Abshire VM, Hankins KD et al (1986) Microinjection of GABA antagonists into posterior hypothalamus elevates heart rate in anesthetized rats. Neuropharmacology 25:1063–1066

    Article  CAS  PubMed  Google Scholar 

  • Fenik VB, Davies RO, Kubin L (2005) REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 172:1322–1330

    Article  PubMed  Google Scholar 

  • Fenik VB, Rukhadze I, Kubin L (2009) Antagonism of α1-adrenergic and serotonergic receptors in the hypoglossal motor nucleus does not prevent motoneuronal activation elicited from the posterior hypothalamus. Neurosci Lett 462:80–84

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Furlong TM, Vianna DM, Liu L, Carrive P (2009) Hypocretin/orexin contributes to the expression of some but not all forms of stress and arousal. Eur J Neurosci 30:1603–1614

    Article  PubMed  Google Scholar 

  • Grimaldi D, Calandra-Buonaura G, Provini F et al (2012) Abnormal sleep-cardiovascular system interaction in narcolepsy with cataplexy: effects of hypocretin deficiency in humans. Sleep 35:519–528

    PubMed Central  PubMed  Google Scholar 

  • Han F, Mignot E, Wei YC et al (2010) Ventilatory chemoresponsiveness, narcolepsy-cataplexy and human leukocyte antigen DQB1*0602 status. Eur Respir J 36:577–583

    Article  CAS  PubMed  Google Scholar 

  • Horvath TL, Peyron C, Diano S et al (1999) Hypocretin (orexin) activation and synaptic innervation of the locus coeruleus noradrenergic system. J Comp Neurol 415:145–159

    Article  CAS  PubMed  Google Scholar 

  • Huang SC, Dai YW, Lee YH et al (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 334:522–529

    Article  CAS  PubMed  Google Scholar 

  • Iigaya K, Horiuchi J, McDowall LM et al (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:R1011–R1022

    CAS  Google Scholar 

  • Johnson PL, Samuels BC, Fitz SD et al (2012) Activation of the orexin 1 receptor is a critical component of CO2-mediated anxiety and hypertension but not bradycardia. Neuropsychopharmacology 37:1911–1922

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Johnson PL, Truitt W, Fitz SD et al (2010) A key role for orexin in panic anxiety. Nat Med 16:111–115

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Kayaba Y, Nakamura A, Kasuya Y et al (2003) Attenuated defense response and low basal blood pressure in orexin knockout mice. Am J Physiol 285:R581–R593

    Google Scholar 

  • Kiyashchenko LI, Mileykovskiy BY, Maidment N et al (2002) Release of hypocretin (orexin) during waking and sleep states. J Neurosci 22:5282–5286

    CAS  PubMed  Google Scholar 

  • Kuwaki T (2008) Orexinergic modulation of breathing across vigilance states. Respir Physiol Neurobiol 164:204–212

    Article  CAS  PubMed  Google Scholar 

  • Kuwaki T (2011) Orexin links emotional stress to autonomic functions. Auton Neurosci Bas Clin 161:20–27

    Article  CAS  Google Scholar 

  • Laitman BM, Gajewski ND, Mann G et al (2014) The alpha1 adrenoceptor antagonist prazosin enhances sleep continuity in fear-conditioned Wistar-Kyoto rats. Progr Neuro-Psychopharmacol Biol Psych 49:7–15

    Article  CAS  Google Scholar 

  • Lazarenko RM, Stornetta RL, Bayliss DA, Guyenet PG (2011) Orexin A activates retrotrapezoid neurons in mice. Respir Physiol Neurobiol 175:283–287

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lee YH, Dai YW, Huang SC et al (2013) Blockade of central orexin 2 receptors reduces arterial pressure in spontaneously hypertensive rats. Exp Physiol 98:1145–1155

    Article  CAS  PubMed  Google Scholar 

  • Li A, Hindmarch CC, Nattie EE, Paton JF (2013) Antagonism of orexin receptors significantly lowers blood pressure in spontaneously hypertensive rats. J Physiol 591:4237–4248

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Lo Martire V, Silvani A, Bastianini S et al (2012) Effects of ambient temperature on sleep and cardiovascular regulation in mice: the role of hypocretin/orexin neurons. PLoS ONE 7:e47032. doi:10.1371/journal.pone.0047032

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Lu JW, Fenik VB, Branconi JL et al (2007) Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats. J Physiol 582:553–567

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Marcus JN, Aschkenasi CJ, Lee CE et al (2001) Differential expression of orexin receptors 1 and 2 in the rat brain. J Comp Neurol 435:6–25

    Article  CAS  PubMed  Google Scholar 

  • McAuley JD, Stewart AL, Webber ES et al (2009) Wistar-Kyoto rats as an animal model of anxiety vulnerability: support for a hypervigilance hypothesis. Behav Brain Res 204:162–168

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Nakamura A, Zhang W, Yanagisawa M et al (2007) Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 102:241–248

    Article  CAS  PubMed  Google Scholar 

  • Nattie E, Li A (2012) Respiration and autonomic regulation and orexin. Progr Brain Res 198:25–46

    Article  CAS  Google Scholar 

  • Nishijima T, Sakurai S, Arihara Z, Takahashi K (2003) Plasma orexin-A-like immunoreactivity in patients with sleep apnea hypopnea syndrome. Peptides 24:407–411

    Article  CAS  PubMed  Google Scholar 

  • Nisimaru N, Mittal C, Shirai Y et al (2013) Orexin-neuromodulated cerebellar circuit controls redistribution of arterial blood flows for defense behavior in rabbits. Proc Natl Acad Sci USA 110:14124–14131

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Peyron C, Tighe DK, van den Pol AN et al (1998) Neurons containing hypocretin (orexin) project to multiple neuronal systems. J Neurosci 18:9996–10015

    CAS  PubMed  Google Scholar 

  • Remmers JE, DeGroot WJ, Sauerland EK, Anch AM (1978) Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 44:931–938

    CAS  PubMed  Google Scholar 

  • Rusyniak DE, Zaretsky DV, Zaretskaia MV et al (2012) The orexin-1 receptor antagonist SB-334867 decreases sympathetic responses to a moderate dose of methamphetamine and stress. Physiol Behav 107:743–750

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sakurai S, Nishijima T, Takahashi S et al (2005) Low plasma orexin-A levels were improved by continuous positive airway pressure treatment in patients with severe obstructive sleep apnea-hypopnea syndrome. Chest 127:731–737

    Article  CAS  PubMed  Google Scholar 

  • 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:R382–R387

    CAS  Google Scholar 

  • Sauerland EK, Harper RM (1976) The human tongue during sleep: electromyographic activity of the genioglossus muscle. Exp Neurol 51:160–170

    Article  CAS  PubMed  Google Scholar 

  • Scammell TE, Winrow CJ (2011) Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol 51:243–266

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Schwimmer H, Stauss HM, Abboud F et al (2010) Effects of sleep on the cardiovascular and thermoregulatory systems: a possible role for hypocretins. J Appl Physiol 109:1053–1063

    Article  CAS  PubMed  Google Scholar 

  • Shahid IZ, Rahman AA, Pilowsky PM (2012) Orexin and central regulation of cardiorespiratory system. Vitam Horm 89:159–184

    Article  CAS  PubMed  Google Scholar 

  • Shekhar A, DiMicco JA (1987) Defense reaction elicited by injection of GABA antagonists and synthesis inhibitors into the posterior hypothalamus in rats. Neuropharmacology 26:407–417

    Article  CAS  PubMed  Google Scholar 

  • Shirasaka T, Kunitake T, Takasaki M, Kannan H (2002) Neuronal effects of orexins: relevant to sympathetic and cardiovascular functions. Regul Pept 104:91–95

    Article  CAS  PubMed  Google Scholar 

  • Silvani A, Bastianini S, Berteotti C et al (2012) Control of cardiovascular variability during undisturbed wake-sleep behavior in hypocretin-deficient mice. Am J Physiol 302:R958–R964

    CAS  Google Scholar 

  • Silvani A, Dampney RA (2013) Central control of cardiovascular function during sleep. Am J Physiol 305:H1683–H1692

    CAS  Google Scholar 

  • Silvani A, Grimaldi D, Barletta G et al (2013) Cardiovascular variability as a function of sleep-wake behaviour in narcolepsy with cataplexy. J Sleep Res 22:178–184

    Article  PubMed  Google Scholar 

  • Sorensen GL, Knudsen S, Petersen ER et al (2013) Attenuated heart rate response is associated with hypocretin deficiency in patients with narcolepsy. Sleep 36:91–98

    PubMed Central  PubMed  Google Scholar 

  • 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 114:119–130

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Stettner GM, Kubin L, Volgin DV (2011) Antagonism of orexin 1 receptors eliminates motor hyperactivity and improves homing response acquisition in juvenile rats exposed to alcohol during early postnatal period. Behav Brain Res 221:324–328

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Sunanaga J, Deng BS, Zhang W et al (2009) CO2 activates orexin-containing neurons in mice. Respir Physiol Neurobiol 166:184–186

    Article  CAS  PubMed  Google Scholar 

  • Takahash K, Lin JS, Sakai K (2008) Neuronal activity of orexin and non-orexin waking-active neurons during wake-sleep states in the mouse. Neuroscience 153:860–870

    Article  Google Scholar 

  • Tarasiuk A, Levi A, Berdugo-Boura N et al (2014) Role of orexin in respiratory and sleep homeostasis during upper airway obstruction in rats. Sleep 37:987–998

    PubMed Central  PubMed  Google Scholar 

  • Williams RH, Jensen LT, Verkhratsky A et al (2007) Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci USA 104:10685–10690

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Wu MF, Nienhuis R, Maidment N et al (2011a) Cerebrospinal fluid hypocretin (orexin) levels are elevated by play but are not raised by exercise and its associated heart rate, blood pressure, respiration or body temperature changes. Arch Ital Biol 149:492–498

    PubMed Central  PubMed  Google Scholar 

  • Wu MF, Nienhuis R, Maidment N et al (2011b) Role of the hypocretin (orexin) receptor 2 (Hcrt-r2) in the regulation of hypocretin level and cataplexy. J Neurosci 31:6305–6310

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  • Xiao F, Jiang M, Du D et al (2013) Orexin A regulates cardiovascular responses in stress-induced hypertensive rats. Neuropharmacology 67:16–24

    Article  CAS  PubMed  Google Scholar 

  • Yamuy J, Fung SJ, Xi M, Chase MH (2004) Hypocretinergic control of spinal cord motoneurons. J Neurosci 24:5336–5345

    Article  CAS  PubMed  Google Scholar 

  • Young JK, Wu M, Manaye KF et al (2005) Orexin stimulates breathing via medullary and spinal pathways. J Appl Physiol 98:1387–1395

    Article  CAS  PubMed  Google Scholar 

  • 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:R1654–R1663

    CAS  Google Scholar 

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Acknowledgments

Our studies summarized in this review were supported by the following grants from the National Institutes of Health: HL-47600, HL-60287, HL-74385 and HL-116508.

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Authors and Affiliations

  1. Department of Animal Biology 209E/VET, School of Veterinary Medicine, 3800 Spruce Street, Philadelphia, PA, 19104-6046, USA

    Leszek Kubin

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  1. Leszek Kubin
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Correspondence to Leszek Kubin .

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Editors and Affiliations

  1. Dept. of Molecular Neurosci. & Integrati, Faculty of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan

    Takeshi Sakurai

  2. Somnogen Canada Inc, President and Chief Executive Officer, Toronto, Ontario, Canada

    S.R. Pandi-Perumal

  3. Dept. Pharmacology & Therapeutics, Clinics Hospital Montevideo School of Medicine, Montevideo, Uruguay

    Jaime M. Monti

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Kubin, L. (2015). Orexinergic Tone in Cardiorespiratory Regulation. In: Sakurai, T., Pandi-Perumal, S., Monti, J. (eds) Orexin and Sleep. Springer, Cham. https://doi.org/10.1007/978-3-319-23078-8_22

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