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Neuropeptide Regulation of Ion Channels and Food Intake
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Orexin/hypocretin is another orexigenic neuropeptide that is produced and released by neurons located in the lateral hypothalamus. Despite the restricted expression of orexin cell body within the hypothalamus, orexin projections are found in a wide range of brain areas involved in feeding and arousal. The lateral hypothalamus synthesizes and releases orexin-A (or hypocretin-1) and orexin-B (or hypocretin-2), two structurally analogous neuropeptides, to exert functional modulation of postsynaptic neurons expressed with orexin receptors (OX1R and OX2R). In addition to orexin, orexin neurons also release dynorphin from the same synaptic vesicles which lead to a complex effect on the postsynaptic neurons (Muschamp et al. 2014; Chou et al. 2001).
Sedative and Hypnotic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Arup Kumar Misra, Pramod Kumar Sharma
Orexin-A and orexin-B commonly known as hypocretin-1 and hypocretin-2, respectively, are neuropeptides that have affinity for OX-1 and OX-2 receptors and has pharmacological role on sleep pattern. They play a promoting role in sleep cycle especially wakefulness, metabolism effects, reward, stress, and autonomic function (Roecker et al., 2016). CNS neurons are quiescent during sleep but are active during wakefulness; thus antagonists at orexin receptors enhance the different stages of sleep. This class of drugs is a newly developed class of hypnotic used for the treatment of sleep disorder. Suvorexant, orexin 1 and 2 receptors antagonist was approved by FDA in late 2014 for the treatment of insomnia (Roecker et al., 2016). Its main pharmacological action is to decrease the time to fall asleep and maintain its total duration. The orexin receptor antagonist suvorexant is metabolized by the CYP3A4 enzymes and also it is a substrate of CYP3A4. Its half-life is prolonged by the presence of enzyme inhibitors like ketoconazole, clarithromycin, and verapamil. The drug strength is 10 mg and it is instructed to be taken before sleep. Daytime somnolence and worsening of depression or suicidal ideation are the most common adverse reaction seen with the drug. Its higher dose may disrupt the driving skills of the patients which may lead to road traffic accident. Some newer molecules are undergoing clinical trials (Vermeeren et al., 2015).
Mood and Food, Cravings, and Addiction
Published in Emily Crews Splane, Neil E. Rowland, Anaya Mitra, Psychology of Eating, 2019
Emily Crews Splane, Neil E. Rowland, Anaya Mitra
An increasing amount of evidence indicates a role of the orexin (also referred to as hypocretin) system in drug abuse and palatable food consumption (Aston-Jones, 2010). Orexin receptors have been found in the hypothalamus (associated with maintaining homeostasis and motivation) and mesolimbic regions (associated with reward). Orexin signaling seems to modulate dopamine activity within the mesolimbic region, enhancing the reward of pleasurable stimuli and increasing the motivation to seek out such stimulation. However, orexin antagonists do not block food-deprived rats’ consumption of chow, indicating that orexin activity is involved in hedonic food consumption and drug use, but not hunger-induced food consumption (Choi et al., 2010).
Brain site-specific regulation of hedonic intake by orexin and DYN peptides: role of the PVN and obesity
Published in Nutritional Neuroscience, 2022
P. Mattar, S. Uribe-Cerda, C. Pezoa, T. Guarnieri, C. M. Kotz, J. A. Teske, E. Morselli, C. Perez-Leighton
The orexin and dynorphin peptides are part of the neuronal network that regulates hedonic intake, the reward-driven choice and intake of palatable food (tasty food rich in fat, sugar or salt) [1–3]. The orexins (orexin-A, OXA and orexin-B) are excitatory neuropeptides synthesized by neurons in the lateral hypothalamus (LH) and released in several brain sites (ventral tegmental area, VTA; paraventricular thalamic nucleus, PVT; central amygdala, CeA) [4] where they can bind to their receptors (OX1R and OX2R) [5] to enhance hedonic intake and the motivation for reinforcers including palatable food [6–9]. The orexin receptors might have specialized functions with OX1R regulating reward and OX2R regulating the effects of orexin peptides on sleep and energy expenditure [10,11]. The opioid dynorphins are inhibitory neuropeptides synthesized by different neurons and promote depressive states and negative consequences of stress [12]. However, the opioid dynorphin peptide DYN-A1–13, which has a higher affinity for the κ-opioid receptor (KOR) subtype but can bind and activate the μ- (MOR) and δ- (DOR) subtypes [13–15], can enhance hedonic intake through different brain sites including the paraventricular hypothalamic nucleus (PVN) [16–20]. In PVN, individual food and nutrient preference modulates hedonic intake caused by activation of MOR and DOR [16,21–23], but whether food preference modulates the feeding effects of DYN-A1–13 is unknown.
Improvement in fatigue and sleep measures with the dual orexin receptor antagonist lemborexant in adults with insomnia disorder
Published in Postgraduate Medicine, 2022
Craig Chepke, Rakesh Jain, Russell Rosenberg, Margaret Moline, Jane Yardley, Kate Pinner, Dinesh Kumar, Carlos Perdomo, Gleb Filippov, Norman Atkins, Manoj Malhotra
To our knowledge, this is the first report on the effect of orexin receptor antagonists on fatigue severity scores in adults with insomnia disorder. The importance of insomnia-related daytime symptoms and resulting impairment of daily functioning is recognized in diagnostic criteria for insomnia disorder, including the ICSD-3 and DSM-5 [7,27]. Clinical guidelines recommend incorporating daytime functional outcomes into drug efficacy trials of insomnia [8]. Nevertheless, fatigue is not a common outcome measure in clinical trials of insomnia therapies [44]. The characteristics of insomnia that are associated with fatigue are still undetermined. A study of such factors found that depression, daytime sleepiness, and prolonged habitual sleep duration were related to fatigue, while there were no correlations between fatigue and any polysomnography measures [45]. Insomnia-related fatigue may also reflect dysfunctional cognition or beliefs about sleep and fatigue, leading to heightened nighttime arousal while in bed and daytime hypervigilance to fatigue [45,46], which may be further aggravated by depressive symptoms [45]. Consequently, it cannot be assumed that treatments effective in improving sleep quality will lead to improvements in daytime fatigue and, therefore, positive changes in fatigue are important potential endpoints in clinical trials.
Rethinking the use of hypnotics for treatment of insomnia in the elderly
Published in Expert Opinion on Pharmacotherapy, 2021
The orexin system has been implicated in the regulation of functions such as feeding behavior, locomotion, physical activity, and arousal from sleep [3]. The levels in cerebrospinal fluid are highest at the end of the wake-period and lowest at the end of sleep. The orexin system stimulates the target neurons in the wake system – leading to the release of several chemicals (dopamine, serotonin, histamine, acetylcholine, norepinephrine) that promote wakefulness [3]. DORAs have shown various effects, including the promotion of natural sleep [28,29] and clearance of waste from the brain [30]. Moreover, DORAs – different to benzodiazepines, Z-drugs, and sedating antidepressants – do not impair physical and cognitive functions after e.g. forced awakening from night-sleep [31,32]. Orexin receptor antagonists therefore will very likely be first-choice agents in the treatment of insomnia with a special emphasis on the prevention of neurodegenerative disorders. Ongoing studies appear to confirm the absence of tolerance development over 12 months.