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Frontiers of Neurology and Neuroscience 2021Sleep is one of the pillars of health. Experimental models of acute sleep loss, of chronic partial sleep deprivation, and of sleep fragmentation in healthy sleepers are... (Review)
Review
Sleep is one of the pillars of health. Experimental models of acute sleep loss, of chronic partial sleep deprivation, and of sleep fragmentation in healthy sleepers are helpful models of sleep deficiency produced by insufficient sleep duration, sleep timing, and sleep disorders. Sleep deficiency is associated with changes in markers associated with risk for disease. These include metabolic, inflammatory, and autonomic markers of risk. In addition, sleep disruption and sleep deficits lead to mood instability, lack of positive outlook, and impaired neurobehavioral functioning. On a population level, insufficient sleep is associated with increased risk for hypertension and diabetes. Sleep disturbance is very common, and about half the population will report that they have experienced insomnia at some time in their lives. Approximately 10% of the population describe daytime impairment due to sleep disturbance at night, consistent with a diagnosis of insomnia disorder. The hypothalamic neuropeptides, orexin-A and orexin-B, act through G-protein-coupled receptors (orexin-1 and orexin-2 receptors). Dual and selective orexin-2 receptor antagonists have shown efficacy in inducing sleep in men and women with insomnia disorder by accelerating sleep onset and improving sleep efficiency and total sleep time. Further study comparing these medications, in short- and longer-term use models, is recommended. Greater understanding of comparative effects on mood, neurobehavioral, and physiological systems will help determine the extent of clinical utility of dual versus selective orexin receptor antagonists.
Topics: Animals; Cardiovascular Diseases; Chronic Pain; Humans; Metabolic Diseases; Orexin Receptor Antagonists; Orexin Receptors; Orexins; Sleep Deprivation; Sleep Initiation and Maintenance Disorders
PubMed: 34052807
DOI: 10.1159/000514956 -
Trends in Endocrinology and Metabolism:... May 2023Orexin (OX)A and OXB are a pair of neuropeptides secreted by orexin-producing neurons in the lateral hypothalamus. The orexin system can regulate many physiological... (Review)
Review
Orexin (OX)A and OXB are a pair of neuropeptides secreted by orexin-producing neurons in the lateral hypothalamus. The orexin system can regulate many physiological processes through these two receptor pathways, such as feeding behavior, sleep/wake state, energy homeostasis, reward, and the coordination of emotion. Mammalian target of rapamycin (mTOR) can coordinate upstream signals with downstream effectors, thereby regulating fundamental cellular processes and also plays an essential role in the signaling network downstream of the orexin system. In turn, the orexin system can activate mTOR. Here, we review the association of the orexin system with the mTOR signaling pathway mainly by discussing that drugs in various diseases exert their effects on the orexin system, indirectly affecting the mTOR signaling pathway.
Topics: Humans; Animals; Orexins; Orexin Receptors; Neuropeptides; Signal Transduction; TOR Serine-Threonine Kinases; Mammals
PubMed: 36934048
DOI: 10.1016/j.tem.2023.02.008 -
Nature Communications May 2022The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism...
The OX orexin receptor (OXR) is a highly expressed G protein-coupled receptor (GPCR) in the brain that regulates wakefulness and circadian rhythms in humans. Antagonism of OXR is a proven therapeutic strategy for insomnia drugs, and agonism of OXR is a potentially powerful approach for narcolepsy type 1, which is characterized by the death of orexinergic neurons. Until recently, agonism of OXR had been considered 'undruggable.' We harness cryo-electron microscopy of OXR-G protein complexes to determine how the first clinically tested OXR agonist TAK-925 can activate OXR in a highly selective manner. Two structures of TAK-925-bound OXR with either a G mimetic or G reveal that TAK-925 binds at the same site occupied by antagonists, yet interacts with the transmembrane helices to trigger activating microswitches. Our structural and mutagenesis data show that TAK-925's selectivity is mediated by subtle differences between OX and OX receptor subtypes at the orthosteric pocket. Finally, differences in the polarity of interactions at the G protein binding interfaces help to rationalize OXR's coupling selectivity for G signaling. The mechanisms of TAK-925's binding, activation, and selectivity presented herein will aid in understanding the efficacy of small molecule OXR agonists for narcolepsy and other circadian disorders.
Topics: Cryoelectron Microscopy; Humans; Narcolepsy; Orexin Receptors; Orexins; Receptors, G-Protein-Coupled; Wakefulness
PubMed: 35614071
DOI: 10.1038/s41467-022-30601-3 -
Medicine Jun 2023Orexin, also known as hypocretin, is an excitatory neuropeptide secreted by the hypothalamus. Orexin is divided into orexin-A (OXA) and orexin-B (OXB), which are derived... (Review)
Review
Orexin, also known as hypocretin, is an excitatory neuropeptide secreted by the hypothalamus. Orexin is divided into orexin-A (OXA) and orexin-B (OXB), which are derived from a common precursor secreted by hypothalamic neurons. Orexin acts on orexin receptor-1 (OX1R) and orexin receptor-2 (OX2R). Orexin neurons, as well as receptors, are widely distributed in various regions of the brain as well as in the peripheral system and have a wider range of functions. This paper reviews the latest research results of orexin in the aspects of food intake, sleep, addiction, depression and anxiety. Because orexin has certain physiological functions in many systems, we further explored the possibility of orexin as a new target for the treatment of bulimia, anorexia nervosa, insomnia, lethargy, anxiety and depression. It is precisely because orexin has physiological functions in multiple systems that orexin, as a new target for the treatment of the above diseases, has potential contradictions. For example, it promotes the function of 1 system and may inhibit the function of another system. How to study a new drug, which can not only treat the diseases of this system, but also do not affect other system functions, is what we need to focus on.
Topics: Humans; Orexins; Orexin Receptors; Cognition; Brain; Anxiety
PubMed: 37390267
DOI: 10.1097/MD.0000000000034206 -
Nutrients Aug 2023Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence... (Review)
Review
Orexin plays a significant role in the modulation of REM sleep, as well as in the regulation of appetite and feeding. This review explores, first, the current evidence on the role of orexin in the modulation of sleep and wakefulness and highlights that orexin should be considered essentially as a neurotransmitter inhibiting REM sleep and, to a much lesser extent, a wake promoting agent. Subsequently, the relationship between orexin, REM sleep, and appetite regulation is examined in detail, shedding light on their interconnected nature in both physiological conditions and diseases (such as narcolepsy, sleep-related eating disorder, idiopathic hypersomnia, and night eating syndrome). Understanding the intricate relationship between orexin, REM sleep, and appetite regulation is vital for unraveling the complex mechanisms underlying sleep-wake patterns and metabolic control. Further research in this field is encouraged in order to pave the way for novel therapeutic approaches to sleep disorders and metabolic conditions associated with orexin dysregulation.
Topics: Appetite; Sleep, REM; Orexins; Appetite Regulation; Sleep
PubMed: 37686711
DOI: 10.3390/nu15173679 -
Nature Communications Jul 2020The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive. Here, we find that a proportion of orexin neurons project to the...
The relationship between orexin/hypocretin and rapid eye movement (REM) sleep remains elusive. Here, we find that a proportion of orexin neurons project to the sublaterodorsal tegmental nucleus (SLD) and exhibit REM sleep-related activation. In SLD, orexin directly excites orexin receptor-positive neurons (occupying ~3/4 of total-population) and increases gap junction conductance among neurons. Their interaction spreads the orexin-elicited partial-excitation to activate SLD network globally. Besides, the activated SLD network exhibits increased probability of synchronized firings. This synchronized excitation promotes the correspondence between SLD and its downstream target to enhance SLD output. Using optogenetics and fiber-photometry, we consequently find that orexin-enhanced SLD output prolongs REM sleep episodes through consolidating brain state activation/muscle tone inhibition. After chemogenetic silencing of SLD orexin signaling, a ~17% reduction of REM sleep amounts and disruptions of REM sleep muscle atonia are observed. These findings reveal a stabilization role of orexin in REM sleep.
Topics: Action Potentials; Animals; Behavior, Animal; Brain Stem; Disease Models, Animal; Electrodes, Implanted; Electroencephalography; Electromyography; Humans; Male; Mice; Mice, Transgenic; Muscle Tonus; Neurons; Optogenetics; Orexin Receptors; Orexins; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Sleep Deprivation; Sleep, REM; Wakefulness
PubMed: 32694504
DOI: 10.1038/s41467-020-17401-3 -
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 -
Nature Neuroscience Jul 2023Brain orexin (hypocretin) neurons are implicated in sleep-wake switching and reward-seeking but their roles in rapid arousal dynamics and reward perception are unclear....
Brain orexin (hypocretin) neurons are implicated in sleep-wake switching and reward-seeking but their roles in rapid arousal dynamics and reward perception are unclear. Here, cell-specific stimulation, deletion and in vivo recordings revealed strong correlative and causal links between pupil dilation-a quantitative arousal marker-and orexin cell activity. Coding of arousal and reward was distributed across orexin cells, indicating that they specialize in rapid, multiplexed communication of momentary arousal and reward states.
Topics: Orexins; Neuropeptides; Pupil; Intracellular Signaling Peptides and Proteins; Neurons
PubMed: 37336973
DOI: 10.1038/s41593-023-01365-w -
Frontiers in Behavioral Neuroscience 2023The postpartum period is a demanding time during which mothers experience numerous physiological adaptations that enable them to care for their offspring while... (Review)
Review
The postpartum period is a demanding time during which mothers experience numerous physiological adaptations that enable them to care for their offspring while maintaining their wellbeing. Hypocretins, also known as orexins, are neuropeptides synthesized by hypothalamic neurons that play a fundamental role in several functions, including the promotion of wakefulness and motivated behaviors, such as maternal care. In this regard, several findings suggest that the activity of the hypocretinergic system increases in the early postpartum period and begins to decline as weaning approaches. In particular, hypocretins within the medial preoptic area, a crucial region during this period, modulate both maternal behavior and sleep. Although further studies are necessary to obtain a comprehensive understanding of the role of hypocretins in lactating females, current research suggests that this system participates in promoting active components of maternal behavior and regulating wakefulness and sleep adjustments during the postpartum period, potentially leading to increased wakefulness during this stage. These adaptive adjustments enable the mother to cope with the continuously changing demands of the pups.
PubMed: 37456808
DOI: 10.3389/fnbeh.2023.1184885 -
Veterinary Sciences Mar 2022Originally named for its expression in the posterior hypothalamus in rats and after the Greek word for "appetite", hypocretin, or orexin, as it is known today, gained... (Review)
Review
Originally named for its expression in the posterior hypothalamus in rats and after the Greek word for "appetite", hypocretin, or orexin, as it is known today, gained notoriety as a neuropeptide regulating feeding behavior, energy homeostasis, and sleep. Orexin has been proven to be involved in both central and peripheral control of neuroendocrine functions, energy balance, and metabolism. Since its discovery, its ability to increase appetite as well as regulate feeding behavior has been widely explored in mammalian food production animals such as cattle, pigs, and sheep. It is also linked to neurological disorders, leading to its intensive investigation in humans regarding narcolepsy, depression, and Alzheimer's disease. However, in non-mammalian species, research is limited. In the case of avian species, orexin has been shown to have no central effect on feed-intake, however it was found to be involved in muscle energy metabolism and hepatic lipogenesis. This review provides current knowledge and summarizes orexin's physiological roles in livestock and pinpoints the present lacuna to facilitate further investigations.
PubMed: 35324840
DOI: 10.3390/vetsci9030112