Orexin stimulates breathing via medullary and spinal pathways

Abstract

stimulates breathing via medullary and spinal pathways. J Appl Physiol 98: 1387-1395, 2005. First published November 19, 2004 doi:10.1152/japplphysiol.00914.2004.-A central neuronal network that regulates respiration may include hypothalamic neurons that produce orexin, a peptide that influences sleep and arousal. In these experiments, we investigated 1) projections of orexin-containing neurons to the pre-Bötzinger region of the rostral ventrolateral medulla that regulates rhythmic breathing and to phrenic motoneurons that innervate the diaphragm; 2) the presence of orexin A receptors in the pre-Bötzinger region and in phrenic motoneurons; and 3) physiological effects of orexin administered into the pre-Bötzinger region and phrenic nuclei at the C3-C4 levels. We found orexin-containing fibers within the pre-Bötzinger complex. However, only 0.5% of orexincontaining neurons projected to the pre-Bötzinger region, whereas 2.9% of orexin-containing neurons innervated the phrenic nucleus. Neurons of the pre-Bötzinger region and phrenic nucleus stained for orexin receptors, and activation of orexin receptors by microperfusion of orexin in either site produced a dose-dependent, significant (P Ͻ 0.05) increase in diaphragm electromyographic activity. These data indicate that orexin regulates respiratory activity and may have a role in the pathophysiology of sleep-related respiratory disorders.hypothalamus; pre-Bötzinger region; phrenic motor neurons; orexin-1 receptors; sleep apnea BREATHING IS AN ACTIVE NEURALLY controlled process that is regulated by neural mechanisms that adjust respiratory-related drive to the behavioral state and to the metabolic demands of an organism. Hypothalamic neurons are part of this controlling system and play an important role in the regulation of breathing rate and depth (14,26).Neurons in the lateral hypothalamus synthesize orexin A and orexin B, also called hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2). These peptide neurotransmitters are processed from a common precursor, prepro-orexin, encoded by a gene localized to human chromosome 17q2. Orexin-containing neurons affect autonomic, neuroendocrine, and sleep-wakefulness neuroregulatory systems that in turn could potentially influence breathing (9,13,16,19).The orexins stimulate target cells via two orexin G proteincoupled receptors, orexin R1 and orexin R2 (40). It has been proposed that orexin-containing neurons promote wakefulness by excitation of cholinergic neurons in the basal forebrain, which release acetylcholine and thereby contribute to the cortical activation of wakefulness. However, the causality of these associations remains to be determined because wakefulness is often accompanied by behavioral activation. Suppression of rapid eye movement sleep occurs through an inhibition of the cholinergic neurons in the laterodorsal tegmental and pedunculopontine nuclei (49).In the central nervous system, orexin-containing neurons innervate multiple sites, including cell groups in the brain stem and spinal cord that are involved in t...

Ventilatory chemoresponsiveness, narcolepsy-cataplexy and human leukocyte antigen DQB1*0602 status

“…Such chemosensory reflexes operate to influence sleep apnoea, chronic obstructive pulmonary disease (COPD), heart failure, and acute adaptation to high altitude [1]. A variation in chemosensitivity across various inbred rodent strains and familial clustering of ventilatory traits in humans provides a strong rationale for gene and protein isolation efforts to unravel molecular mechanisms for these traits operating in health and disease [2].Hypocretin (orexin) is a hypothalamic neurotransmitter, which, when given intracerebroventricularly in mice, promotes both wakefulness and ventilation [3,4]. Both hypocretin knockout and hypocretin neuron-ablated mice show attenuation of respiratory excitation during fightor-flight responses [5].…”

“…Hypocretin (orexin) is a hypothalamic neurotransmitter, which, when given intracerebroventricularly in mice, promotes both wakefulness and ventilation [3,4]. Both hypocretin knockout and hypocretin neuron-ablated mice show attenuation of respiratory excitation during fightor-flight responses [5].…”

Integration in the PVN: another piece of the puzzle

“…It receives inputs, either directly or indirectly, from rostral brain regions, including the limbic system and amygdala, and caudal brain stem regions such as the nucleus tractus solitarius (A2 region), A5 region of the pons, the rostral ventrolateral medulla (RVLM), and locus ceruleus (17,20,30,(35)(36)(37)(38). Outputs to autonomic regions that modulate sympathetic nervous system and cardiovascular function have been extensively described (10,27,35,39,40,42). In contrast, less research has focused on the role of the PVN in control of breathing.…”

“…These include further elucidation of what are the neural pathways and neurotransmitters involved in the physiological responses to peripheral chemoreceptor stimulation. Because there are a large number of neurotransmitters in specific subnuclei of the PVN, excitatory candidates may include oxytocin, vasopressin, leptin, ANG II (possibly acting on ANG I receptors), TRH, CRF, and NMDA among others (8,9,11,12,20,33,34,42). Another question may include what other hypothalamic nuclei are involved in chemoreflex responses.…”

Paroxetine influences respiration in rats: implications for the treatment of panic disorder

“…Axons of orexin-containing neurons project to respiration-related sites, such as the nucleus tractus solitarius, pre-Bötzinger complex, and the hypoglossal, raphe, retrotrapezoid, and phrenic nuclei (Berthoud et al 2005;Fung et al 2001;Peyron et al 1998;Young et al 2005). Intracerebroventricular administration of orexin promotes respiration (Zhang et al 2005) and orexin-deficient mice exposed to stressors increase their respiration less as compared to control mice (Kayaba et al 2003;Zhang et al 2006b).…”