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Trends in Neurosciences Nov 2021Although originally implicated in appetite and sleep/wakefulness, the hypothalamic orexin (hypocretin) system has now been demonstrably linked with motivated behavior....
Although originally implicated in appetite and sleep/wakefulness, the hypothalamic orexin (hypocretin) system has now been demonstrably linked with motivated behavior. This highly plastic system responds to reward-associated environmental stimuli and becomes pathologically overactive in addicted states. Here, we provide a brief overview of the roles of the orexin system in reward-seeking and addiction, as well as potential therapeutic opportunities for substance use disorders based on normalizing orexin function.
Topics: Humans; Hypothalamus; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Wakefulness
PubMed: 34642086
DOI: 10.1016/j.tins.2021.09.002 -
Cellular and Molecular Neurobiology Mar 2018In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several... (Review)
Review
In this review, we focus on the role of orexin signaling in blood pressure control and its potential link to hypertension by summarizing evidence from several experimental animal models of hypertension. Studies using the spontaneously hypertensive rat (SHR) animal model of human essential hypertension show that pharmacological blockade of orexin receptors reduces blood pressure in SHRs but not in Wistar-Kyoto rats. In addition, increased activity of the orexin system contributes to elevated blood pressure and sympathetic nerve activity (SNA) in dark-active period Schlager hypertensive (BPH/2J) mice, another genetic model of neurogenic hypertension. Similar to these two models, Sprague-Dawley rats with stress-induced hypertension display an overactive central orexin system. Furthermore, upregulation of the orexin receptor 1 increases firing of hypothalamic paraventricular nucleus neurons, augments SNA, and contributes to hypertension in the obese Zucker rat, an animal model of obesity-related hypertension. Finally, we propose a hypothesis for the implication of the orexin system in salt-sensitive hypertension. All of this evidence, coupled with the important role of elevated SNA in increasing blood pressure, strongly suggests that hyperactivity of the orexin system contributes to hypertension.
Topics: Animals; Blood Pressure; Disease Models, Animal; Humans; Hypertension; Mice; Orexin Receptors; Orexins; Rats; Rats, Inbred SHR; Rats, Zucker
PubMed: 28349223
DOI: 10.1007/s10571-017-0487-z -
Hypertension (Dallas, Tex. : 1979) Dec 2022Inadequate sleep duration and quality are associated with reduced cardiovascular health and increased mortality. Experimental evidence points to the sympathetic nervous... (Review)
Review
Inadequate sleep duration and quality are associated with reduced cardiovascular health and increased mortality. Experimental evidence points to the sympathetic nervous system as a key mediator in the observed relationship between poor sleep and cardiovascular dysfunction. However, brain mechanisms underpinning the impaired sympathetic function associated with poor sleep remain unclear. Recent evidence suggests the central orexin system, particularly orexins A and B and their receptors, have a key regulatory role for sleep in animal and human models. While orexin system activity has been observed to significantly impact sympathetic regulation in animals, the extension of these findings to humans has been difficult due to an inability to directly assess orexin system activity in humans. However, direct measures of sympathetic activity in populations with narcolepsy and chronic insomnia, 2 sleep disorders associated with deficient and excessive orexin neural activity, have allowed indirect assessment of the relationships between orexin, sleep, and sympathetic regulation. Further, the recent pharmaceutical development of dual orexin receptor antagonists for use in clinical insomnia populations offers an unprecedented opportunity to examine the mechanistic role of orexin in sleep and cardiovascular health in humans. The current review assesses the role of orexin in both sleep and sympathetic regulation from a translational perspective, spanning animal and human studies. The review concludes with future research directions necessary to fully elucidate the mechanistic role for orexin in sleep and sympathetic regulation in humans.
Topics: Animals; Humans; Orexins; Orexin Receptors; Orexin Receptor Antagonists; Sleep; Sleep Initiation and Maintenance Disorders; Sympathetic Nervous System
PubMed: 36148653
DOI: 10.1161/HYPERTENSIONAHA.122.19796 -
Frontiers of Neurology and Neuroscience 2021Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases.... (Review)
Review
Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep in different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose to neurodegenerative disorders such as Alzheimer's disease (AD), and vice versa. New theories on the link between sleep and β-amyloid and tau secretion, accumulation and clearance, and its interaction with hypocretins/orexins (key neuropeptides regulating wakefulness) suggest mechanistic ways to better understand the impact of sleep alterations in the pathogenesis of AD. Further studies should validate whether changes in circadian rhythm and sleep-wakefulness patterns could be used for early AD diagnosis and as prognostic markers for cognitive decline. Longitudinal studies are needed, not only to validate these biomarker interactions and to determine the cause-effect relationship and the role of sleep-wakefulness behavior in the regulation of amyloid plaque and neurofibrillary tangle formation, but also to identify the best sleep therapies and related preventive strategies for AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Glymphatic System; Humans; Narcolepsy; Orexins; Sleep Wake Disorders; tau Proteins
PubMed: 34052817
DOI: 10.1159/000514967 -
Frontiers of Neurology and Neuroscience 2021
Topics: Humans; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Sleep; Sleep Initiation and Maintenance Disorders
PubMed: 34052818
DOI: 10.1159/000514968 -
Frontiers in Neuroendocrinology Oct 2018The neuropeptides orexins are important in regulating the neurobiological systems that respond to stressful stimuli. Furthermore, orexins are known to play a role many... (Review)
Review
The neuropeptides orexins are important in regulating the neurobiological systems that respond to stressful stimuli. Furthermore, orexins are known to play a role many of the phenotypes associated with stress-related mental illness such as changes in cognition, sleep-wake states, and appetite. Interestingly, orexins are altered in stress-related psychiatric disorders such as Major Depressive Disorder and Anxiety Disorders. Thus, orexins may be a potential target for treatment of these disorders. In this review, we will focus on what is known about the role of orexins in acute and repeated stress, in stress-induced phenotypes relevant to psychiatric illness in preclinical models, and in stress-related psychiatric illness in humans. We will also briefly discuss how orexins may contribute to sex differences in the stress response and subsequent phenotypes relevant to mental health, as many stress-related psychiatric disorders are twice as prevalent in women.
Topics: Animals; Anxiety Disorders; Depressive Disorder, Major; Female; Humans; Hypothalamo-Hypophyseal System; Male; Orexins; Pituitary-Adrenal System; Stress, Psychological
PubMed: 29932958
DOI: 10.1016/j.yfrne.2018.06.003 -
International Journal of Molecular... Apr 2022Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including... (Review)
Review
Sleep and wakefulness are basic behavioral states that require coordination between several brain regions, and they involve multiple neurochemical systems, including neuropeptides. Neuropeptides are a group of peptides produced by neurons and neuroendocrine cells of the central nervous system. Like traditional neurotransmitters, neuropeptides can bind to specific surface receptors and subsequently regulate neuronal activities. For example, orexin is a crucial component for the maintenance of wakefulness and the suppression of rapid eye movement (REM) sleep. In addition to orexin, melanin-concentrating hormone, and galanin may promote REM sleep. These results suggest that neuropeptides play an important role in sleep-wake regulation. These neuropeptides can be divided into three categories according to their effects on sleep-wake behaviors in rodents and humans. (i) Galanin, melanin-concentrating hormone, and vasoactive intestinal polypeptide are sleep-promoting peptides. It is also noticeable that vasoactive intestinal polypeptide particularly increases REM sleep. (ii) Orexin and neuropeptide S have been shown to induce wakefulness. (iii) Neuropeptide Y and substance P may have a bidirectional function as they can produce both arousal and sleep-inducing effects. This review will introduce the distribution of various neuropeptides in the brain and summarize the roles of different neuropeptides in sleep-wake regulation. We aim to lay the foundation for future studies to uncover the mechanisms that underlie the initiation, maintenance, and end of sleep-wake states.
Topics: Galanin; Intracellular Signaling Peptides and Proteins; Neuropeptides; Orexins; Sleep; Vasoactive Intestinal Peptide
PubMed: 35562990
DOI: 10.3390/ijms23094599 -
Frontiers of Neurology and Neuroscience 2021Orexins have received a lot of attention as potent endogenous arousal-promoting peptides, and orexin receptor antagonists have shown clinical efficacy for the treatment... (Review)
Review
Orexins have received a lot of attention as potent endogenous arousal-promoting peptides, and orexin receptor antagonists have shown clinical efficacy for the treatment of insomnia. Orexin neurons are thought to act primarily on monoaminergic neurons to maintain arousal and vigilance. In this chapter, we discuss the functional interaction between monoaminergic systems, including noradrenaline, serotonin and histamine, and orexin neurons, as well as interactions between the acetylcholine system and the orexin neurons, focusing, in particular, on their function in the regulation of sleep-wakefulness states. Orexin also has close interactions with the dopaminergic system, and many studies have suggested roles of orexin signaling in the reward system and roles for orexins in drug addiction.
Topics: Acetylcholine; Animals; Biogenic Monoamines; Brain; Humans; Neurons; Orexin Receptors; Orexins
PubMed: 34052806
DOI: 10.1159/000514955 -
Frontiers in Endocrinology 2022At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were... (Review)
Review
At the end of the 20th century, two new neuropeptides (Orexin-A/hypocretin-1 and Orexin-B/hypocretins-2) expressed in hypothalamus as a prepro-orexins precursor, were discovered. These two neuropeptides interacted with two G protein-coupled receptor isoforms named OX1R and OX2R. The orexins/OX receptors system play an important role in the central and peripheral nervous system where it controls wakefulness, addiction, reward seeking, stress, motivation, memory, energy homeostasis, food intake, blood pressure, hormone secretions, reproduction, gut motility and lipolysis. Orexins and their receptors are involved in pathologies including narcolepsy type I, neuro- and chronic inflammation, neurodegenerative diseases, metabolic syndrome, and cancers. Associated with these physiopathological roles, the extensive development of pharmacological molecules including OXR antagonists, has emerged in association with the determination of the structural properties of orexins and their receptors. Moreover, the identification of OX1R expression in digestive cancers encompassing colon, pancreas and liver cancers and its ability to trigger mitochondrial apoptosis in tumoral cells, indicate a new putative therapeutical action of orexins and paradoxically OXR antagonists. The present review focuses on structural and anti-tumoral aspects of orexins and their receptors.
Topics: Humans; Neoplasms; Neuropeptides; Orexin Receptors; Orexins; Receptors, G-Protein-Coupled
PubMed: 35966051
DOI: 10.3389/fendo.2022.931970 -
Handbook of Clinical Neurology 2021The hypocretins/orexins were discovered in 1998. Within 2 years, this led to the discovery of the cause of human narcolepsy, a 90% loss of hypothalamic neurons... (Review)
Review
The hypocretins/orexins were discovered in 1998. Within 2 years, this led to the discovery of the cause of human narcolepsy, a 90% loss of hypothalamic neurons containing these peptides. Further work demonstrated that these neurons were not simply linked to waking. Rather these neurons were active during pleasurable behaviors in waking and were silenced by aversive stimulation. This was seen in wild-type mice, rats, cats, and dogs. It was also evident in humans, with increased Hcrt release during pleasurable activities and decreased release, to the levels seen in sleep, during pain. We found that human heroin addicts have, on average, an increase of 54% in the number of detectable Hcrt neurons compared to "control" human brains and that these Hcrt neurons are substantially smaller than those in control brains. We found that in mice, chronic morphine administration induced the same changes in Hcrt neuron number and size. Our studies in the mouse allowed us to determine the specificity, dose response relations, time course of the change in the number of Hcrt neurons, and that the increased number of Hcrt neurons after opiates was not due to neurogenesis. Furthermore, we found that it took a month or longer for these anatomical changes in the mouse brain to return to baseline. Human narcoleptics, despite their prescribed use of several commonly addictive drugs, do not show significant evidence of dose escalation or substance use disorder. Similarly, mice in which the peptide has been eliminated are resistant to addiction. These findings are consistent with the concept that an increased number of Hcrt neurons may underlie and maintain opioid or cocaine use disorders.
Topics: Animals; Cats; Dogs; Humans; Hypothalamus; Mice; Narcolepsy; Neurons; Orexins; Pleasure; Rats
PubMed: 34225941
DOI: 10.1016/B978-0-12-820107-7.00022-7