Respiratory and cardiovascular actions of orexin-A in mice.
ABSTRACT Ample evidence has been reported to show a probable contribution of orexin in the central cardiovascular regulation. Although cardiovascular and respiratory centers in the brain are located close to each other and are interconnected, the possible participation of orexin in respiratory regulation has not been fully documented. Here we examined the effects of intracerebroventricular administration of orexin-A on respiratory and cardiovascular parameters in urethane-anesthetized mice. Respiratory frequency and tidal volume were recorded simultaneously with blood pressure and heart rate. Orexin-A (0.003-3 nmol in 2 microL) or vehicle was administered into the lateral ventricle or cisterna magna. Lateral ventricular administration induced a rise in respiratory frequency (by 11% at the highest dose), tidal volume (76%), blood pressure (13%) and heart rate (6%) in a dose-dependent manner. With intracisternal administration, however, respiratory frequency did not change while a similar increase in tidal volume (75%) was observed. A relatively larger cardiovascular response was elicited with intracisternal administration (blood pressure 26%, heart rate 9%). On the other hand, with either administration route, orexin-A did not affect reflex increases in respiratory frequency and tidal volume in response to hypoxia and hypercapnia. These results show possible participation of orexin-A not only in the cardiovascular regulation but also in the respiratory control system. Moreover, orexin can affect the cardiorespiratory control system at multiple sites in different ways. Orexin-A seems not to be involved in respiratory reflex regulation in mice at least under anesthetized condition.
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ABSTRACT: Orexin/hypocretin peptide mutations are rare in humans. Even though human narcolepsy is associated with orexin deficiency, this is only extremely rarely due to mutations in the gene coding prepro-orexin, the precursor for both orexin peptides. In contrast, coding and non-coding variants of the OX1 and OX2 orexin receptors have been identified in many human populations; sometimes, these have been associated with disease phenotype, although most confer a relatively low risk. In most cases, these studies have been based on a candidate gene hypothesis that predicts the involvement of orexins in the relevant pathophysiological processes. In the current review, the known human OX1/HCRTR1 and OX2/HCRTR2 genetic variants/polymorphisms as well as studies concerning their involvement in disorders such as narcolepsy, excessive daytime sleepiness, cluster headache, polydipsia-hyponatremia in schizophrenia, and affective disorders are discussed. In most cases, the functional cellular or pharmacological correlates of orexin variants have not been investigated-with the exception of the possible impact of an amino acid 10 Pro/Ser variant of OX2 on orexin potency-leaving conclusions on the nature of the receptor variant effects speculative. Nevertheless, we present perspectives that could shape the basis for further studies. The pharmacology and other properties of the orexin receptor variants are discussed in the context of GPCR signaling. Since orexinergic therapeutics are emerging, the impact of receptor variants on the affinity or potency of ligands deserves consideration. This perspective (pharmacogenetics) is also discussed in the review.Frontiers in Neuroscience 01/2014; 8:57.
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ABSTRACT: Hypocretins, also named as orexins, are excitatory neuropeptides secreted by neurons specifically located in lateral hypothalamus and perifornical areas. Orexinergic fibers are extensively distributed in various brain regions and involved in a number of physiological functions, such as arousal, cognition, stress, appetite, and metabolism. Arousal is the most important function of orexin system as dysfunction of orexin signaling leads to narcolepsy. In addition to narcolepsy, orexin dysfunction is associated with serious neural disorders, including addiction, depression, and anxiety. However, some results linking orexin with these disorders are still contradictory, which may result from differences of detection methods or the precision of tools used in measurements; strategies targeted to orexin system (e.g., antagonists to orexin receptors, gene delivery, and cell transplantation) are promising new tools for treatment of neuropsychiatric disorders, though studies are still in a stage of preclinical or clinical research.Medicinal Research Reviews 07/2014; · 9.58 Impact Factor
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ABSTRACT: Endogenous neuropeptides known as orexins (hypocretins) play important roles in the regulation of feeding, drinking, endocrine function, and sleep/wakefulness. Orexin neuron projection sites include the rostral ventrolateral medulla of brainstem, which is related to the control of breathing. Previous studies suggest that orexins modulate the central CO2 ventilatory response during wakefulness in rodent. In the present sudy, we examined the effects of the orexinergic system on central respiratory control by adding orexin into a superfusion medium in the isolated brain stem-spinal cord of neonatal rat. Exposure to orexin B resulted in dose-dependent increases in C4 burst rate via brainstem, but not spinal cord. These increases in C4 burst rate induced concomitant increases in the depolarizing cycle rate of preinspiratory (Pre-I) and inspiratory (Insp) neurons. Tonic discharge was induced on C4 recording, although the rhythmic bursts of Pre-I and Insp neurons were maintained. Expiratory (Exp) neurons were also depolarized on administration of orexin B. Our findings indicate that orexin B activates central respiratory activity, mainly through depolarization and decreases in membrane resistance in Pre-I and Insp neurons, and possibly through early initiation of the expiratory phase induced by depolarization of Exp neurons.Respiratory Physiology & Neurobiology 06/2014; · 2.05 Impact Factor