Role of Orexin in Respiratory and Sleep Homeostasis during Upper Airway Obstruction in Rats

Tarasiuk, Ariel; Levi, Avishag; Berdugo-Boura, Nilly; Yahalom, Ari; Segev, Yael

doi:10.5665/sleep.3676

Cited by 20 publications

(59 citation statements)

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“…Orexin neurons contribute to the regulation of cardiorespiratory centers and can be upstream of parasympathetic drive . We reported previously that the number of orexin‐immunopositive neurons is increased in KO mice (pooled SD 27‐65 ) when compared with WT .…”

Section: Resultsmentioning

confidence: 97%

“…Orexin neurons project onto numerous respiratory nuclei including rostral ventrolateral medulla, medullary raphe, locus coeruleus, and nucleus tractus solitarius, and they act on orexin G‐protein–coupled receptors 1 and 2. Orexin neurons increase breathing rate in response to hypercapnia and hypoxia, and the administration of DORA reduces this response . Extracellular multielectrode recording data indicate that the chemosensitivity of putative orexin neurons is increased in high‐risk KO mice (TJ.…”

Section: Discussionmentioning

confidence: 99%

“…Orexin neurons increase breathing rate in response to hypercapnia and hypoxia, [25][26][27]34,[36][37][38][39]62 and the administration of DORA reduces this response. 28,29 Extracellular multielectrode recording data indicate that the chemosensitivity of putative orexin neurons is increased in high-risk KO mice (TJ. Warren, KA.…”

Section: Discussionmentioning

confidence: 99%

“…Orexin neurons contribute to the regulation of cardiorespiratory centers and can be upstream of parasympathetic drive. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] We reported previously that the number of orexin-immunopositive F I G U R E 2 Blocking orexin receptors differentially influences heart rate (HR) in knockout (KO) mice. A, A representative brightfield photomicrograph depicting orexin-immunopositive neurons in the lateral hypothalamus at 20x magnification.…”

Section: Lh Is Increased By Sd 30mentioning

confidence: 99%

“…We previously found that KO mice exhibit respiratory abnormalities including increased hypopnea and apnea in high-risk KO mice. 15 Orexin neurons also regulate central respiratory centers [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] ;therefore we determined the effect of DORA treatment on KO respiration. The number of subjects that experienced hypopnea and apnea increased with age, affecting 75%-100% of SD 55 KO mice ( Figure 3A), supporting previous findings.…”

Section: Dual Orexin Receptor Antagonist Differentially Influences mentioning

confidence: 99%

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Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

et al. 2020

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Objective Immediately preceding sudden unexpected death in epilepsy (SUDEP), patients experienced a final generalized tonic‐clonic seizure (GTCS), rapid ventilation, apnea, bradycardia, terminal apnea, and asystole. Whether a progressive pathophysiology develops and increases risk of SUDEP remains unknown. Here, we determined (a) heart rate, respiratory rate, and blood oxygen saturation (SaO2) in low‐risk and high‐risk knockout (KO) mice; and (b) whether blocking receptors for orexin, a cardiorespiratory neuromodulator, influences cardiorespiratory function mice or longevity in high‐risk KO mice. Methods Heart rate and SaO2 were determined noninvasively with ECGenie and pulse oximetry. Respiration was determined with noninvasive airway mechanics technology. The role of orexin was determined within subject following acute treatment with a dual orexin receptor antagonist (DORA, 100 mg/kg). The number of orexin neurons in the lateral hypothalamus was determined with immunohistochemistry. Results Intermittent bradycardia was more prevalent in high‐risk KO mice, an effect that may be the result of increased parasympathetic drive. High‐risk KO mice had more orexin neurons in the lateral hypothalamus. Blocking of orexin receptors differentially influenced heart rate in KO, but not wild‐type (WT) mice. When DORA administration increased heart rate, it also decreased heart rate variability, breathing frequency, and/or hypopnea‐apnea. Blocking orexin receptors prevented the methacholine (MCh)–induced increase in breathing frequency in KO mice and reduced MCh‐induced seizures, via a direct or indirect mechanism. DORA improved oxygen saturation in KO mice with intermittent hypoxia. Daily administration of DORA to high‐risk KO mice increased longevity. Significance High‐risk KO mice have a unique cardiorespiratory phenotype that is characterized by progressive changes in five interdependent endpoints. Blocking of orexin receptors attenuates some of these endpoints and increases longevity, supporting the notion that windows of opportunity for intervention exist in this preclinical SUDEP model.

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Section: Resultsmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Lh Is Increased By Sd 30mentioning

confidence: 99%

Section: Dual Orexin Receptor Antagonist Differentially Influences mentioning

confidence: 99%

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Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

et al. 2020

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Orexin in Respiratory and Autonomic Regulation, Health and Diseases

Lusk

2020

Comprehensive Physiology

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Orexin neurons, located in the hypothalamus, produce orexin-A and orexin-B neuropeptides and send widespread projections throughout the central nervous system, including many nuclei that are critically involved in sleep-wake, cardiorespiratory, and autonomic regulation. Significant progress has been made to better understand the roles of orexins in the control of breathing and autonomic functions since the discovery of orexins in 1998. Orexin neurons are CO 2 /pH chemosensitive and blockade of orexin receptors with orexin receptor antagonists can significantly attenuate ventilatory response to hypercapnia or CO 2 chemoreflex. Animal models with orexin abnormalities, for example, too little or too much, have all been reported to have significant alterations in breathing, central chemoreception (hypercapnic chemoreflex), blood pressure, thermoregulation, and cardiorespiratory responses to stress. More recent studies further show that abnormalities of the orexin system are linked to many neurological disorders in addition to narcolepsy, for example, sleep disorders, neurodegenerative disorders, neurogenic hypertension, and sudden infant death syndrome. These new findings have significantly advanced the knowledge in understanding the underlying mechanism of orexin-associated health and diseases while providing a new pathway for possible treatments. In this article, we will discuss some of the progresses in basic research and in health and diseases.

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Orexin and Central Modulation of Cardiovascular and Respiratory Function

Carrive

Kuwaki

2016

Current Topics in Behavioral Neurosciences

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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.

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Role of Orexin in Respiratory and Sleep Homeostasis during Upper Airway Obstruction in Rats

Abstract: In upper airway obstruction animals, enhanced orexin secretion, while crucially important for respiratory homeostasis maintenance, is also responsible for chronic partial sleep loss, as well as considerable impairment of energy metabolism and growth.

Cited by 20 publications

References 54 publications

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

Progressive cardiorespiratory dysfunction in Kv1.1 knockout mice may provide temporal biomarkers of pending sudden unexpected death in epilepsy (SUDEP): The contribution of orexin

Orexin in Respiratory and Autonomic Regulation, Health and Diseases

Orexin and Central Modulation of Cardiovascular and Respiratory Function

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