Orexin and Central Regulation of Cardiorespiratory System

doi:10.1016/B978-0-12-394623-2.00009-3

Vitamins & Hormones

Volume 89, 2012, Pages 159-184

https://doi.org/10.1016/B978-0-12-394623-2.00009-3 Get rights and content

Abstract

The hypothalamic peptide orexin plays a role in many physiological systems including feeding behavior, sleep–wakefulness, reward system, stress, and nociception. In addition, it is now clear that orexin is involved in the central regulation of cardiorespiratory function. Here, we review the cardiorespiratory effects elicited by central orexin and consider the physiological role of this peptide in central cardiorespiratory control in normal and pathophysiological states. Orexin neurons are found exclusively in the hypothalamus but project to almost all brain regions including cardiorespiratory regulatory areas, where their receptors are also expressed. Administration of orexin into the nucleus tractus solitarius, rostral ventrolateral medulla, rostral ventromedial medulla, and spinal cord increases blood pressure, heart rate, and sympathetic nerve activity. Orexin neurons stimulate respiration and are sensitive to changes in pH. Orexin knockout mice have apnoeic episodes in sleep. Therefore, orexin may be a potentially important therapeutic target for the treatment of cardiorespiratory disorders.

Introduction

Since it was first identified only 13 years ago as ligands of two orphan G-protein-coupled receptors (GPCRs), orexins (also known as hypocretins) are implicated in a wide range of physiological processes including sleep–wakefulness, feeding, energy homeostasis, pain, metabolism, and hormonal secretion (de Lecea et al., 1998, Sakurai et al., 1998). A growing body of evidence suggests that orexins are involved in certain aspects of cardiovascular and respiratory functions. In this review, we will discuss the role of orexin on central autonomic function emphasizing on central regulation of cardiovascular and respiratory system, and consider the physiological role of orexin with respect to cardiorespiratory functioning in different physiological and pathophysiological states.

Section snippets

Orexins

Orexin A and orexin B (also called hypocretin 1 and hypocretin 2) were first identified in 1998 by two separate groups via two different approaches (Alexander et al., 2011, de Lecea et al., 1998, Sakurai et al., 1998). In current review, we will use the term orexin, which is derived from the Greek word “orexis,” meaning “appetite.” Orexins were so named for their stimulatory role in feeding (Sakurai et al., 1998). Both orexin A and orexin B are produced by proteolytic cleavage of the gene

Connections of Orexins with Other Transmitters

Orexin neurons in the hypothalamus are innervated by a variety of upstream neuronal populations including those involved in feeding, reward system, sleep–wakefulness, and memory and emotional state regulation. Some of the important brain regions innervating orexin neurons include the basal forebrain (BF) cholinergic neurons, GABA-containing neurons in the ventrolateral preoptic area (VLPO), neurons in the dorsomedial/posterior hypothalamus, VTA neurons, and serotonergic neurons in the raphe

In feeding behavior and energy homeostasis

There is a considerable body of evidence for the role of orexin in the regulation of feeding and energy homeostasis. Orexinergic cell bodies are located in the LHA that is a known feeding center. Orexin and orexin receptor immunoreactivity have also been found in the brain regions involved in food intake and energy homeostasis including Arc, VMH, DMH, and PVN suggesting a greater orexin contribution (Cutler et al., 1999, Elias et al., 1998, Marcus et al., 2001, Nambu et al., 1999, Peyron et

Central Cardiovascular Effects of Orexin

The distribution of orexins, and orexin receptors, in the cardiovascular regulatory centers, as well as functional studies indicate a crucial role of orexin in the regulation of autonomic function. Orexin neurons in the hypothalamus project to PVN and to different brainstem nuclei involved in control of sympathetic and parasympathetic outflow including NTS, RVMM, RVLM, and NA and to the final relay center of sympathetic tone, that is, sympathetic preganglionic neurons of the spinal cord (

Respiratory Effects of Orexin

The role of hypothalamic orexin system in the regulation of breathing is well recognized from both anatomical and functional evidence. Axons of orexin neurons project to respiratory-related nuclei including RVLM sympathoexcitatory neurons, pre-Bötzinger complex (part of respiratory rhythm generator), the NTS (area containing inspiratory cells responsive to sensory afferents), retrotrapezoid nucleus (RTN; central chemoreceptor), raphe nuclei (an area regulating respiratory long-term

Conclusion

Successful homeostatic regulation requires, inter alia, delicate interactions between neuroendocrine systems and central autonomic control pathways. Minor changes in any system will cause feedback changes in others. After more than a decade of research, orexin neurons have emerged as a crucial neurophysiological link between energy balance, emotion, reward systems, and arousal. Active waking causes increases in HR, MAP, respiration, and locomotor activity. However, the neural mechanisms and

Acknowledgments

Work in the Authors’ laboratory is supported by Grants from the National Health and Medical Research Council of Australia (1024489, 1030297, 9201100439, 604002), Australian Research Council (DP110102110, LP120100463), and Macquarie University. A. A. Rahman and I. Z. Shahid are supported by a Macquarie University Research Excellence Scholarship.

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This research reports on the membrane interactions of orexin A (OXA), an α-helical and amphipathic neuropeptide that contains 33 residues and two disulfide bonds in the N-terminal region. OXA, which activates the orexins 1 and 2 receptors in neural and immune cell membranes, has essential pleiotropic physiological effects, including at the levels of arousal, sleep/wakefulness, energy balance, neuroprotection, lipid signaling, the inflammatory response, and pain. As a result, the orexin system has become a prominent target to treat diseases such as sleep disorders, drug addiction, and inflammation. While the high-resolution structure of OXA has been investigated in water and bound to micelles, there is a lack of information about its conformation bound to phospholipid membranes and its receptors. NMR is a powerful method to investigate peptide structures in a membrane environment. To facilitate the NMR structural studies of OXA exposed to membranes, we present a novel synthetic scheme, leading to the production of isotopically-labeled material at high purity. A receptor activation assay shows that the ¹⁵N-labeled peptide is biologically active. Biophysical studies are performed using surface plasmon resonance, circular dichroism, and NMR to investigate the interactions of OXA with phospholipid bilayers. The results demonstrate a strong interaction between the peptide and phospholipids, an increase in α-helical content upon membrane binding, and an in-plane orientation of the C-terminal region critical to function. This new knowledge about structure-activity relationships in OXA could inspire the design of novel therapeutics that leverage the anti-inflammatory and neuro-protective functions of OXA, and therefore could help address neuroinflammation, a major issue associated with neurological disorders such as Alzheimer's disease.
The role of monoaminergic neurons in modulating respiration during sleep and the connection with SUDEP
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The D2 receptors, which mediate sleep–wake regulation and seizure inhibition, may be a potential target for preventing SUDEP. Orexin neurons are mainly located in the LHA [182], and their fibers are widely projected to various brain regions involved in arousal, playing a key role in regulating sleep–wake [183]. In the CNS, inhibition between the sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) and the wake active neurons represented by monoaminergic neurons is crucial to the sleep–wake transition.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death among epilepsy patients, occurring even more frequently in cases with anti-epileptic drug resistance. Despite some advancements in characterizing SUDEP, the underlying mechanism remains incompletely understood. This review summarizes the latest advances in our understanding of the pathogenic mechanisms of SUDEP, in order to identify possible targets for the development of new strategies to prevent SUDEP. Based on our previous research along with the current literature, we focus on the role of sleep-disordered breathing (SDB) and its related neural mechanisms to consider the possible roles of monoaminergic neurons in the modulation of respiration during sleep and the occurrence of SUDEP. Overall, this review suggests that targeting the monoaminergic neurons is a promising approach to preventing SUDEP. The proposed roles of SDB and related monoaminergic neural mechanisms in SUDEP provide new insights for explaining the pathogenesis of SUDEP.
Behavioural and cardiovascular effects of orexin-A infused into the central amygdala under basal and fear conditions in rats
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To date, studies focused on OX’s cardiovascular effects have been relatively restricted to hypothalamus and brainstem. Efferent structures that have been identified following microinfusion of OX-A include medullary raphe, rostral ventral medulla, paraventricular and arcuate hypothalamic areas, and diagonal band of Broca [20,21,46–51]. In contrast, OX-A microinfusion into nucleus of the solitary tract, subfornical organ and nucleus ambiguus reduces heart rate [23–25,52], which not only suggests that OX has multiple sites of action for cardiovascular responses, but also has different functional outcomes at its terminal regions.
The neuropeptide orexin-A (OX-A) has diverse functions, including maintaining arousal, autonomic control, motor activity and stress responses. These functions are regulated at different terminal regions where OX-A is released. The current study examined the physiological and behavioural effects of OX-A microinjections into the central amygdala (CeA) under basal and stressed conditions in rats. When OX-A was microinjected into the CeA and the animals returned to the home-cage, heart rate and mean arterial pressure were increased compared to vehicle-injected controls. General activity of the animal was also increased, indicating that OX-A activity in CeA contributes to increased arousal. This outcome is similar to the effects of central intracerebroventricular infusions of OX-A, as well as the cardiovascular effects previously demonstrated at many of OX’s efferent hypothalamic and brainstem structures. In a second study, animals were fear-conditioned to a context by delivery of electric footshocks and then animals were re-exposed to the conditioned context at test. When OX-A was microinjected at test, freezing behaviour was reduced and there was a corresponding increase in the animal’s activity but no impact on the pressor and cardiac responses (i.e, blood pressure and heart rate were unchanged). This reduction in freezing suggests that OX-A activates amygdala neurons that inhibit freezing, which is similar to the actions of other neuropeptides in the CeA that modulate the appropriate defence response to fearful stimuli. Overall, these data indicate that the CeA is an important site of OX-A modulation of cardiovascular and motor activity, as well as conditioned freezing responses.
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In addition to their role in regulating arousal states, ORX peptides are involved in the control of feeding, metabolism, reward, stress, and ANS activity (Winsky-Sommerer et al., 2005; Samson and Resch, 2000; Girault et al., 2012; Giardino and de Lecea, 2014). Microinjection of ORX into the rostral ventrolateral medulla increases blood pressure, heart rate, and sympathetic nervous system activity (Shahid et al., 2012). ORX neurons in the PFLH are labeled following injections of retrograde tracer into the raphe pallidus and microinjection of ORX-A into the raphe pallidus causes sustained increases in BAT sympathetic outflow and BAT thermogenesis (Tupone et al., 2011).
Sleep in mammals is accompanied by a decrease in core body temperature (CBT). The circadian clock in the hypothalamic suprachiasmatic nucleus regulates daily rhythms in both CBT and arousal states, and these rhythms are normally coupled. Reductions in metabolic heat production resulting from behavioral quiescence and reduced muscle tone along with changes in autonomic nervous system activity and thermoeffector activity contribute to the sleep-related fall in CBT. Reductions in sympathetic tone to the peripheral vasculature resulting in heat loss through the skin are reflected in a sleep-related increase in distal skin temperature that is a prominent feature of sleep onset in humans. Within a sleep episode, patterns of autonomic nervous system and thermoeffector activity and the ability to defend against heat and cold exposure differ during nonrapid eye movement (NREM) and rapid eye movement sleep. Anatomic and functional integration of the control of arousal states and thermoregulation occur in the preoptic/anterior hypothalamus. Subsets or warm-sensing neurons in the preoptic/anterior hypothalamus implicated in CBT regulation are spontaneously activated during sleep onset and NREM sleep compared to waking and may underlie sleep-related changes in autonomic nervous system and thermoeffector activity.
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The peptides orexin A (OxA) and orexin B (OxB) deriving from a common precursor molecule, prepro-orexin, by proteolytic cleavage, bind the two G-coupled OX₁ and OX₂ receptors. While OX₁ selectively binds OxA, OX₂ shows similar affinity for both orexins. Firstly discovered in the hypothalamus, orexins and their receptors have been found in other brain regions as well as in peripheral tissues of mammals, thus resulting involved in the regulation of a broad variety of physiological functions. While the functional localization of OxA and OX₁ in the mammalian genital tract has been already described, the expression of OxB and OX₂ and their potential role in the reproductive functions remain to be explored. Here, we investigated the presence of OxB and OX₂ in the rat testis by immunohistochemical and biochemical analyses. The results definitely demonstrated the localization of OxB and OX₂ in pachytene and second spermatocytes as well as in spermatids at all stages of the cycle of the seminiferous epithelium. The expression of both OX₂ mRNA and protein in the rat testis was also established by RT-PCR and Western blotting, respectively. The analysis of the molecular mechanism of action of OxB in the rat testis showed that OxB, in contrast with OxA, is unable to promote steroidogenesis. These results translate into the regulation of diverse biological actions by OxA and OxB in the male gonad.
Medullary mediation of the laryngeal adductor reflex: A possible role in sudden infant death syndrome
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Citation Excerpt :
The sensory inputs from the SLN are processed within the medulla oblongata (Loewy and Burton, 1978; Dutschmann et al., 2014; Wang et al., 2015), pons (Bautista and Dutschmann, 2014; Dutschmann et al., 2004; Miyaoka et al., 1998), and forebrain (Peden and Sweazey, 1999). The medulla oblongata is a critical site for the generation and regulation of respiratory and cardiovascular control, the laryngeal reflex and many other important visceral activities (Bautista et al., 2014; Berkowitz et al., 2005; Calaresu et al., 1975; Farnham and Pilowsky, 2010; Gaede and Pilowsky, 2010; Li et al., 2005; Makeham et al., 2005; Miyawaki et al., 2003; Padley et al., 2003; Pascual-Font et al., 2011; Pilowsky, 2014; Rahman et al., 2013; Shahid et al., 2012; Spirovski et al., 2012; Springell et al., 2005; Sun et al., 2003; Verner et al., 2004). The medulla oblongata is considered crucial for the LAR.
The laryngeal adductor reflex (LAR) is a laryngeal protective reflex. Vagal afferent polymodal sensory fibres that have cell bodies in the nodose ganglion, originate in the sub-glottal area of the larynx and upper trachea. These polymodal sensory fibres respond to mechanical or chemical stimuli. The central axons of these sensory vagal neurons terminate in the dorsolateral subnuclei of the tractus solitarius in the medulla oblongata. The LAR is a critical, reflex in the pathways that play a protective role in the process of ventilation, and the sychronisation of ventilation with other activities that are undertaken by the oropharyngeal systems including: eating, speaking and singing. Failure of the LAR to operate properly at any time after birth can lead to SIDS, pneumonia or death. Despite the critical nature of this reflex, very little is known about the central pathways and neurotransmitters involved in the management of the LAR and any disorders associated with its failure to act properly.
Here, we review current knowledge concerning the medullary nuclei and neurochemicals involved in the LAR and propose a potential neural pathway that may facilitate future SIDS research.

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Chapter Nine - Orexin and Central Regulation of Cardiorespiratory System

Abstract

Introduction

Section snippets

Orexins

Connections of Orexins with Other Transmitters

In feeding behavior and energy homeostasis

Central Cardiovascular Effects of Orexin

Respiratory Effects of Orexin

Conclusion

Acknowledgments

Peptides

Pain

Regul. Pept.

Neuron

Mol. Brain Res.

Neurosci. Lett.

Brain Res.

Regul. Pept.

Peptides

Neurosci. Lett.

Brain Res.

Domest. Anim. Endocrinol.

Neuroscience

Neuroscience

Brain Res.

Neuron

Neurosci. Lett.

Regul. Pept.

Neuroscience

FEBS Lett.

Neuron

Neuroscience

Neuron

Horm. Behav.

J. Biol. Chem.

Regul. Pept.

J. Steroid Biochem. Mol. Biol.

Biochem. Biophys. Res. Commun.

Brain Res.

Brain Res.

Regul. Pept.

Life Sci.

Biochem. Biophys. Res. Commun.

Neurobiol. Dis.

Regul. Pept.

Cell

J. Biol. Chem.

Neuron

Brain Res.

Glucagon-like peptide 1 excites hypocretin/orexin neurons by direct and indirect mechanisms: Implications for viscera-mediated arousal

J. Neurosci.

Guide to receptors and channels (GRAC)

Br. J. Pharmacol.

Orexins/hypocretins excite rat sympathetic preganglionic neurons in vivo and in vitro

Am. J. Physiol.

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

Eur. J. Neurosci.

Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABAA receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment

Eur. J. Neurosci.

Cellular localization of orexin receptors in human pituitary

J. Clin. Endocrinol. Metab.

Hypocretin/Orexin- and melanin-concentrating hormone-expressing cells form distinct populations in the rodent lateral hypothalamus: Relationship to the neuropeptide Y and agouti gene-related protein systems

J. Comp. Neurol.

Convergent excitation of dorsal raphe serotonin neurons by multiple arousal systems (orexin/hypocretin, histamine and noradrenaline)

J. Neurosci.

Physiological changes in glucose differentially modulate the excitability of hypothalamic melanin-concentrating hormone and orexin neurons in situ

J. Neurosci.

Hypothalamic orexin expression: Modulation by blood glucose and feeding

Diabetes

Pressor effects of orexins injected intracisternally and to rostral ventrolateral medulla of anesthetized rats

Am. J. Physiol.

Activation of a subpopulation of orexin/hypocretin-containing hypothalamic neurons by GABA_A receptor-mediated inhibition of the nucleus accumbens shell, but not by exposure to a novel environment