Chapter Nine - Orexin and Central Regulation of Cardiorespiratory System
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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The role of monoaminergic neurons in modulating respiration during sleep and the connection with SUDEP
2022, Biomedicine and PharmacotherapyCitation Excerpt :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.
Behavioural and cardiovascular effects of orexin-A infused into the central amygdala under basal and fear conditions in rats
2021, Behavioural Brain ResearchCitation Excerpt :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.
Body temperature and sleep
2018, Handbook of Clinical NeurologyCitation Excerpt :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).
Expression of orexin B and its receptor 2 in rat testis
2017, General and Comparative EndocrinologyMedullary mediation of the laryngeal adductor reflex: A possible role in sudden infant death syndrome
2016, Respiratory Physiology and NeurobiologyCitation 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.