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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).
Sleep–Wake Disorders
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
Margaret Kay-Stacey, Eunice Torres-Rivera, Phyllis C. Zee
Ascending reticular activating system: wakefulness (Figure 28.10; Table 28.1). Location: brainstem, lateral/posterior hypothalamus, basal forebrain.The orexin- (also known as hypocretin) secreting neurons are key to maintenance of wakefulness. (Figure 28.11) These neurons have wide-ranging activating projections to the wake promoting brain, and inhibitory to sleep promoting regions, such as the ventrolateral preoptic (VLPO) nucleus (see below).
Sedative and Hypnotic Drugs
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Arup Kumar Misra, Pramod Kumar Sharma
Filorexant (MK-6096) a promising agent acting antagonist at orexin receptor for the treatment of sleep disorders. It acts on OX-1 and OX-2 receptors as a dual antagonist. It improves the sleep pattern of the patient as it induces sleep and decreases locomotor activity. It was not developed beyond Phase II clinical trials which might be due to the cost in its drug development or due to its unwanted side effects (Kathryn et al., 2017).
Persistent effects of the orexin-1 receptor antagonist SB-334867 on naloxone precipitated morphine withdrawal symptoms and nociceptive behaviors in morphine dependent rats
Published in International Journal of Neuroscience, 2021
Masoumeh Kourosh-Arami, Mohammad-Taghi Joghataei, Alireza Komaki, Masoumeh Gholami, Zohreh Najafi, Mostafa Lavaie
Orexins are neurotransmitters with an important role in drug addiction [1–3]. Orexin A is a well-known peptide in the lateral hypothalamus (LH). It is involved in feeding, wake cycle [4,5], and reward-related processes, including drug abuse and addiction [4–14]. Orexin neuropeptides activate OXR1 and orexin type 2 (OXR2) receptors, which are G-protein coupled receptors [15]. OXR1 has a higher affinity to orexin-A than orexin-B, while OXR2 has the same affinity for both peptides [15]. In one-week old animals, only a small subset of neurons in the LH are orexin-A positive [16]. Based on previous studies, translation of orexin mRNA can be detected at very low levels on the day of birth, followed by a rise to the maximum at PND20 [17]. Furthermore, glucosensitivity [18] of LH neurons and their response to sensory afferents [19] mature during PND0 to 3. Therefore, orexin might play an important role in the response and reaction of LH during development [17].
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.
Orexin A ameliorates HBV X protein-induced cytotoxicity and inflammatory response in human hepatocytes
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2019
Li Wang, Tao He, Baishun Wan, Xiaoqian Wang, Ling Zhang
Orexin A is a small peptide with 33 amino acids and two disulfide bonds. Orexin A acts by activating its two GCPR receptors, OX1R and OX2R. However, OX1R has a much greater affinity for orexin A than OX2R (100–1000 times), suggesting that the two receptors play different roles [7]. Indeed, the two orexin receptors play varied roles in different tissues and cells [8]. Orexin A and activation of its receptors were shown to be the central regulators of food intake, energy homeostasis and wake-sleeping cycle. Recently growing evidence suggests that orexin A has a major function in peripheral tissues. According to previous studies, orexin A and its receptors are expressed in hepatocytes and involved in the regulation of normal liver function and disease progression. In rat hepatocytes, orexin A activates OX1R expression, promotes cell proliferation, and offers protection against apoptotic stimuli [9]. Orexin A also stimulates glucose utilization in the liver and in cultured hepatocytes by upregulating glucose transporter GLUT-4 [10]. Liver metastases have higher OX1R mRNA and the presence of orexin A induces cancer cells apoptosis [11]. Orexin A also facilitates glucose flux into mitochondria and promotes oxidative metabolism in HepG2 cancer cells [12]. In a prediabetes mouse model, the administration of orexin A has been shown to prevent hepatic insulin resistance [13]. The most recent study showed that orexin A may contribute to the regulation of lipid metabolism in the liver as orexin A knockout mice exhibit greater weight gain [14].