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https://www.readbyqxmd.com/read/28526554/the-roles-of-orexins-in-sleep-wake-regulation
#1
REVIEW
Michihiro Mieda
Orexin A and orexin B are hypothalamic neuropeptides initially identified as endogenous ligands for two orphan G-protein coupled receptors (GPCRs). A deficiency of orexin signaling results in the sleep disorder narcolepsy-cataplexy in humans, dogs, and rodents, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. Multiple approaches, including molecular genetic, electrophysiological, pharmacological, and neuroanatomical studies have suggested that orexins play critical roles in the maintenance of wakefulness by regulating the function of monoaminergic and cholinergic neurons that are implicated in the regulation of wakefulness...
May 16, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28526553/hypothalamic-regulation-of-the-sleep-wake-cycle
#2
REVIEW
Daisuke Ono, Akihiro Yamanaka
Sleep is one of the most important physiological functions in mammals. It is regulated by not only homeostatic regulation but also circadian clock. Several neuropeptide-producing neurons located in the hypothalamus are implicated in the regulation of sleep/wakefulness. Among them, orexin/hypocretin-producing neurons (orexin neurons) are a crucial component for maintenance of wakefulness, because lack of orexin function results in narcolepsy, which is a sleep disorder. Recent findings have identified substances that excite or inhibit neural activity of orexin neurons...
May 16, 2017: Neuroscience Research
https://www.readbyqxmd.com/read/28520464/suvorexant-for-the-treatment-of-insomnia-in-adolescents
#3
Kentaro Kawabe, Fumie Horiuchi, Marina Ochi, Kayoko Nishimoto, Shu-Ichi Ueno, Yasunori Oka
OBJECTIVES: Suvorexant is the first dual orexin receptor antagonist for treating insomnia. This study aimed to evaluate the tolerability, efficacy, and safety of suvorexant on insomnia in adolescents. METHODS: Thirty patients (8 male and 22 female; mean standard deviation age: 15.7 ± 2.4 years; range: 10-20) with insomnia were administered suvorexant. Clinical background, persistence rate, the Clinical Global Impression (CGI), and the Athens Insomnia Scale (AIS) were compared between patients who continued and discontinued suvorexant treatment...
May 18, 2017: Journal of Child and Adolescent Psychopharmacology
https://www.readbyqxmd.com/read/28509114/implicating-the-potential-role-of-orexin-in-hypertension
#4
REVIEW
Monika Rani, Raghuvansh Kumar, Pawan Krishan
Orexins (orexin A and orexin B), neuropeptides of hypothalamic origin also known as hypocretins, have been well documented for regulating the different physiological functions including feeding, sleep wakefulness, stress, and reward. However, from the past few years, orexins have evolved as an emerging biomarker for various endocrine disorders including diabetes mellitus and obesity which ultimately leads to various cardiovascular risk factors. Orexins exist in two isoforms orexin A and orexin B and exert their effect by acting on the G protein-coupled receptors orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R)...
May 16, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28507129/nonpeptide-orexin-type-2-receptor-agonist-ameliorates-narcolepsy-cataplexy-symptoms-in-mouse-models
#5
Yoko Irukayama-Tomobe, Yasuhiro Ogawa, Hiromu Tominaga, Yukiko Ishikawa, Naoto Hosokawa, Shinobu Ambai, Yuki Kawabe, Shuntaro Uchida, Ryo Nakajima, Tsuyoshi Saitoh, Takeshi Kanda, Kaspar Vogt, Takeshi Sakurai, Hiroshi Nagase, Masashi Yanagisawa
Narcolepsy-cataplexy is a debilitating disorder of sleep/wakefulness caused by a loss of orexin-producing neurons in the lateroposterior hypothalamus. Genetic or pharmacologic orexin replacement ameliorates symptoms in mouse models of narcolepsy-cataplexy. We have recently discovered a potent, nonpeptide OX2R-selective agonist, YNT-185. This study validates the pharmacological activity of this compound in OX2R-transfected cells and in OX2R-expressing neurons in brain slice preparations. Intraperitoneal, and intracerebroventricular, administration of YNT-185 suppressed cataplexy-like episodes in orexin knockout and orexin neuron-ablated mice, but not in orexin receptor-deficient mice...
May 15, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28487995/c-terminus-of-ox2r-significantly-affects-downstream-signaling-pathways
#6
Chunmei Wang, Chao Xu, Minghui Liu, Yanyou Pan, Bo Bai, Jing Chen
The human orexin 2 receptor (OX2R) is a G-protein‑coupled receptor (GPCR) that has been implicated in a number of diverse physiological functions. Recent studies have identified a number of functions of the C‑termini of GPCRs. However, the importance of the OX2R C‑terminus in regulating signaling and surface expression remains unclear. In the present study, the function of the OX2R C‑terminus was investigated using three C‑terminal mutants, which were truncated at residues 368, 384 and 414, respectively, and the wild‑type control, which expressed the full‑length OX2R...
May 9, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/28485844/neuropeptides-and-neurotransmitters-that-modulate-thalamo-cortical-pathways-relevant-to-migraine-headache
#7
REVIEW
Rodrigo Noseda, David Borsook, Rami Burstein
Dynamic thalamic regulation of sensory signals allows the cortex to adjust better to rapidly changing behavioral, physiological, and environmental demands. To fulfill this role, thalamic neurons must themselves be subjected to constantly changing modulatory inputs that originate in multiple neurochemical pathways involved in autonomic, affective, and cognitive functions. This review defines a chemical framework for thinking about the complexity of factors that modulate the response properties of relay trigeminovascular thalamic neurons...
May 2017: Headache
https://www.readbyqxmd.com/read/28460015/rare-missense-mutations-in-p2ry11-in-narcolepsy-with-cataplexy
#8
Matilda Degn, Yves Dauvilliers, Karin Dreisig, Régis Lopez, Corinne Pfister, Sylvain Pradervand, Birgitte Rahbek Kornum, Mehdi Tafti
The sleep disorder narcolepsy with cataplexy is characterized by a highly specific loss of hypocretin (orexin) neurons, leading to the hypothesis that the condition is caused by an immune or autoimmune mechanism. All genetic variants associated with narcolepsy are immune-related. Among these are single nucleotide polymorphisms in the P2RY11-EIF3G locus. It is unknown how these genetic variants affect narcolepsy pathogenesis and whether the effect is directly related to P2Y11 signalling or EIF3G function. Exome sequencing in 18 families with at least two affected narcolepsy with cataplexy subjects revealed non-synonymous mutations in the second exon of P2RY11 in two families, and P2RY11 re-sequencing in 250 non-familial cases and 135 healthy control subjects revealed further six different non-synonymous mutations in the second exon of P2RY11 in seven patients...
April 27, 2017: Brain: a Journal of Neurology
https://www.readbyqxmd.com/read/28453642/facilitation-of-contextual-fear-extinction-by-orexin-1-receptor-antagonism-is-associated-with-the-activation-of-specific-amygdala-cell-subpopulations
#9
África Flores, Cyril Herry, Rafael Maldonado, Fernando Berrendero
Background: Orexins are hypothalamic neuropeptides recently involved in the regulation of emotional memory. The basolateral amygdala (BLA), an area orchestrating fear memory processes, appears to be modulated by orexin transmission during fear extinction. However, the neuronal types within the BLA involved in this modulation remain to be elucidated. Methods: We used retrograde tracing combined with immunofluorescence techniques in mice to identify BLA projection neurons and cell subpopulations in this brain region influenced by orexin transmission during contextual fear extinction consolidation...
April 27, 2017: International Journal of Neuropsychopharmacology
https://www.readbyqxmd.com/read/28448426/orexin-receptor-antagonism-in-painful-diabetic-neuropathy-a-phase-2-trial-with-filorexant
#10
W Joseph Herring, Joy Y Ge, Saheeda Jackson, Christopher Assaid, Kathryn M Connor, David Michelson
OBJECTIVES: To evaluate whether orexin receptor antagonism with filorexant provides pain relief in patients with painful diabetic neuropathy (PDN). METHODS: In this double-blind, placebo-controlled, enriched-enrollment, randomized-withdrawal proof-of-concept study, patients with PDN (aged 18-75 y) entered a 2-week, single-blind active run-in period with filorexant 10 mg nightly, before randomization 1:1 to placebo or filorexant in a 2-week, double-blind treatment period...
April 26, 2017: Clinical Journal of Pain
https://www.readbyqxmd.com/read/28447885/recovery-from-coma-post-cardiac-arrest-is-dependent-on-the-orexin-pathway
#11
Young-Jin Kang, Guilian Tian, Afsheen Bazrafkan, Maryam H Farahabadi, Matine Azadian, Hamidreza Abbasi, Brittany Shamaoun, Oswald Steward, Yama Akbari
Cardiac arrest affects >550,000 people annually in the USA while 80-90% of survivors suffer from a comatose state. Arousal from coma is critical for recovery but mechanisms of arousal are undefined. Orexin-A, a hypothalamic excitatory neuropeptide, has been linked to arousal deficits in various brain injuries. We investigated the orexinergic system's role in recovery from cardiac arrest-related neurological impairments, including arousal deficits. Using an asphyxial cardiac arrest and resuscitation model in rats, we examine neurological recovery post-resuscitation in conjunction with changes in orexin-A levels in cerebrospinal fluid and orexin-expressing neurons...
April 27, 2017: Journal of Neurotrauma
https://www.readbyqxmd.com/read/28445807/rewiring-brain-circuits-to-block-cataplexy-in-murine-models-of-narcolepsy
#12
REVIEW
Meng Liu, Carlos Blanco-Centurion, Priyattam J Shiromani
Narcolepsy was first identified almost 130 years ago, but it was only 15 years ago that it was identified as a neurodegenerative disease linked to a loss of orexin neurons in the brain. It is unclear what causes the orexin neurons to die, but our strategy has been to place the gene for orexin into surrogate neurons in the validated mouse models of narcolepsy, and test whether it can block narcolepsy symptoms, such as cataplexy. In both the orexin knockout and the orexin-ataxin-3 mouse models of narcolepsy we have found that cataplexy can be blocked if the surrogate neurons are part of the circuit responsible for cataplexy...
April 23, 2017: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/28444767/the-dual-orexin-receptor-antagonist-dora-22-lowers-histamine-levels-in-the-lateral-hypothalamus-and-prefrontal-cortex-without-lowering-hippocampal-acetylcholine
#13
Lihang Leon Yao, Andres Ramirez, Anthony J Roecker, Steven Fox, Jason Uslaner, Sean M Smith, Robert Hodgson, Paul J Coleman, John J Renger, Christopher J Winrow, Anthony L Gotter
Chronic insomnia is defined as a persistent difficulty with sleep initiation maintenance or non-restorative sleep. The therapeutic standard of care for this condition is treatment with gamma-aminobutyric acid (GABA)A receptor modulators, which promote sleep but are associated with a panoply of side effects, including cognitive and memory impairment. Dual orexin receptor antagonists (DORAs) have recently emerged as an alternative therapeutic approach that acts via a distinct and more selective wake-attenuating mechanism with the potential to be associated with milder side effects...
April 26, 2017: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28442349/perinatal-programming-of-the-orexinergic-hypocretinergic-system-in-hypothalamus-and-anterior-pituitary-by-testosterone
#14
Natalia I Cataldi, Victoria A Lux-Lantos, Carlos Libertun
Orexins A/B derived from hypothalamic prepro-orexin (PPO) are agonists for orexin receptors 1 (OX1) and 2 (OX2). Previously, we showed clear sex differences in the hypothalamic-pituitary-gonadal orexinergic system in adult rodents. Here, we studied the effect of sexual brain differentiation on the orexinergic system in neuroendocrine structures regulating reproduction. We evaluated: a: proestrous and neonatally androgenized female rats; b: adult males, untreated or gonadectomized in adulthood and injected with oil or estradiol and progesterone (E2/P4); c: control and demasculinized males (perinatally treated with flutamide and later castration) injected either with oil or E2/P4 in adulthood...
April 22, 2017: Peptides
https://www.readbyqxmd.com/read/28427826/suvorexant-in-elderly-patients-with-insomnia-pooled-analyses-of-data-from-phase-iii-randomized-controlled-clinical-trials
#15
W Joseph Herring, Kathryn M Connor, Ellen Snyder, Duane B Snavely, Ying Zhang, Jill Hutzelmann, Deborah Matzura-Wolfe, Ruth M Benca, Andrew D Krystal, James K Walsh, Christopher Lines, Thomas Roth, David Michelson
OBJECTIVE: Suvorexant is an orexin receptor antagonist approved for treating insomnia at doses of 10-20 mg. Previously reported phase III results showed that suvorexant was effective and well-tolerated in a combined-age population (elderly and nonelderly adults). The present analysis evaluated the clinical profile of suvorexant specifically in the elderly. METHODS: Prespecified subgroup analyses of pooled 3-month data from two (efficacy) and three (safety) randomized, double-blind, placebo-controlled, parallel-group trials...
March 8, 2017: American Journal of Geriatric Psychiatry
https://www.readbyqxmd.com/read/28427008/lateral-hypothalamic-circuits-for-sleep-wake-control
#16
REVIEW
Takayuki Yamashita, Akihiro Yamanaka
The lateral hypothalamic area (LHA) of the diencephalon is crucially involved in controlling instinctive behavior such as sleep-wake cycle and feeding behavior. LHA is a heterogeneous structure that contains spatially intermingled, genetically distinct cell populations. Among LHA neurons, orexin/hypocretin (OX) neuron is the key cell type that promotes waking, and specific loss of OX neurons results in narcolepsy. Melanin-concentrating hormone (MCH) containing neurons are known to be active during rapid eye movement (REM) sleep and stimulation of these neurons promotes REM sleep...
April 17, 2017: Current Opinion in Neurobiology
https://www.readbyqxmd.com/read/28420957/neuropeptide-y-induced-orexigenic-action-is-attenuated-by-the-orexin-receptor-antagonist-in-bullfrog-larvae
#17
Kouhei Matsuda, Kairi Matsumura, Syun-Suke Shimizu, Tomoya Nakamachi, Norifumi Konno
In bullfrog larvae at the pre- and pro-metamorphic stages, feeding behavior is regulated by appetite factors such as orexigenic peptides. In fact, food intake is enhanced by intracerebroventricular (ICV) administration of neuropeptide Y (NPY) and orexin A. Using goldfish, our previous study indicated that the orexigenic action of NPY is mediated by orexin A, suggesting the functional interaction between the two. However, there is little information about whether the action of orexin A mediates the orexigenic action of NPY in bullfrog larvae...
2017: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/28419646/suvorexant-an-orexin-hypocretin-receptor-antagonist-attenuates-motivational-and-hedonic-properties-of-cocaine
#18
Taylor A Gentile, Steven J Simmons, David J Barker, Jessica K Shaw, Rodrigo A España, John W Muschamp
Orexins ('hypocretins') are peptides produced by neurons of the hypothalamus that project to structures implicated in reward and emotion processing. Converging evidence demonstrates functional roles of orexin signaling in arousal, sleep/wakefulness and motivated behaviors for natural and drug rewards. Suvorexant, a dual orexin receptor antagonist, recently received approval from the US Food and Drug Administration to treat insomnia. In Experiment 1, rats self-administered cocaine under a progressive-ratio schedule of reinforcement and the effects of suvorexant on motivation to self-administer cocaine were measured...
April 17, 2017: Addiction Biology
https://www.readbyqxmd.com/read/28416460/regional-distribution-of-cholinergic-catecholaminergic-serotonergic-and-orexinergic-neurons-in-the-brain-of-two-carnivore-species-the-feliform-banded-mongoose-mungos-mungo-and-the-caniform-domestic-ferret-mustela-putorius-furo
#19
Sashrika Pillay, Adhil Bhagwandin, Mads F Bertelsen, Nina Patzke, Gerhard Engler, Andreas K Engel, Paul R Manger
The nuclear organization of the cholinergic, catecholaminergic, serotonergic and orexinergic neurons in the brains of two species of carnivore, the banded mongoose (Mungos mungo) and domestic ferret (Mustela putorius furo), is presented. The banded mongoose belongs to the feliform suborder and the domestic ferret to the caniform suborder, having last shared a common ancestor approximately 53 million years ago; however, they have a very similar overall morphology and life history, presenting an interesting opportunity to examine the extent of evolutionary plasticity in these systems...
April 14, 2017: Journal of Chemical Neuroanatomy
https://www.readbyqxmd.com/read/28414966/modeling-sleep-and-neuropsychiatric-disorders-in-zebrafish
#20
REVIEW
Talia Levitas-Djerbi, Lior Appelbaum
What are the molecular and cellular mechanisms that link neurological disorders and sleep disturbances? The transparent zebrafish model could bridge this gap in knowledge due to its unique genetic and imaging toolbox, and amenability to high-throughput screening. Sleep is well-characterized in zebrafish and key regulators of the sleep/wake cycle are conserved, including melatonin and hypocretin/orexin (Hcrt), whereas novel sleep regulating proteins are continually being identified, such as Kcnh4a, Neuromedin U, and QRFP...
April 14, 2017: Current Opinion in Neurobiology
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