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Elham Kordijaz, Ali Moghimi, Masoud Fereidoni, Saeedeh Asadi, Ali Shamsizadeh, Ali Roohbakhsh
Convulsive seizures are due to abnormal synchronous and repetitive neuronal discharges in the central nervous system (CNS). Finding new therapeutics to overcome the side effects of the current drug therapies and to increase their effectiveness is ongoing. Orexin-A and orexin-B are brain neuropeptides originating from postero-lateral hypothalamic neurons. Studies show that orexins, through activation of OX1 and OX2 receptors, have excitatory effects in the CNS. Accordingly, the present study was designed to evaluate the effect of OX1 receptor antagonist (SB-334867) on seizure- and anxiety-related behaviors of pentylenetetrazol (PTZ) kindled rats...
October 14, 2016: Fundamental & Clinical Pharmacology
Masaru Ishibashi, Iryna Gumenchuk, Kenichi Miyazaki, Takafumi Inoue, William N Ross, Christopher S Leonard
UNLABELLED: Orexins (hypocretins) are neuropeptides that regulate multiple homeostatic processes, including reward and arousal, in part by exciting serotonergic dorsal raphe neurons, the major source of forebrain serotonin. Here, using mouse brain slices, we found that, instead of simply depolarizing these neurons, orexin-A altered the spike encoding process by increasing the postspike afterhyperpolarization (AHP) via two distinct mechanisms. This orexin-enhanced AHP (oeAHP) was mediated by both OX1 and OX2 receptors, required Ca(2+) influx, reversed near EK, and decayed with two components, the faster of which resulted from enhanced SK channel activation, whereas the slower component decayed like a slow AHP (sAHP), but was not blocked by UCL2077, an antagonist of sAHPs in some neurons...
September 28, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Kelly Lei, Scott A Wegner, Ji Hwan Yu, Arisa Mototake, Bing Hu, Frederic W Hopf
Addiction to alcohol remains a major social and economic problem, in part because of the high motivation for alcohol that humans exhibit and the hazardous binge intake this promotes. Orexin-1-type receptors (OX1Rs) promote reward intake under conditions of strong drives for reward, including excessive alcohol intake. While systemic modulation of OX1Rs can alter alcohol drinking, the brain regions that mediate this OX1R enhancement of excessive drinking remain unknown. Given the importance of the nucleus accumbens (NAc) and anterior insular cortex (aINS) in driving many addictive behaviors, including OX1Rs within these regions, we examined the importance of OX1Rs in these regions on excessive alcohol drinking in C57BL/6 mice during limited-access alcohol drinking in the dark cycle...
2016: Frontiers in Neuroscience
Ainoleena Turku, Alexandre Borrel, Teppo O Leino, Lasse Karhu, Jyrki P Kukkonen, Henri Xhaard
Small molecule agonists and antagonists of the orexinergic system have key implications for research and therapeutic purposes. We report a pharmacophore model trained on ∼200 antagonists and prospectively validated by screening a collection of ∼137,000 compounds. The resulting hit list, 395 compounds, was tested for OX1 and OX2 receptor activity using calcium mobilization assay in recombinant cell lines. Validation was conducted using both calcium mobilization and [(125)I]-orexin-A competition binding. Compounds 4-7 have weak agonist activity and Ki's in the 1-30 μM range; compounds 8-14 are antagonists with Ki's in the 0...
September 22, 2016: Journal of Medicinal Chemistry
Kelly Lei, Scott A Wegner, Ji-Hwan Yu, F Woodward Hopf
Addiction is promoted by pathological motivation for addictive substances, and, despite extensive efforts, alcohol use disorders (AUDs) continue to extract a very high social, physical, and economic toll. Compulsive drinking of alcohol, where consumption persists even when alcohol is paired with negative consequences, is considered a particular obstacle for treating AUDs. Aversion-resistant alcohol intake in rodents, e.g. where rodents drink even when alcohol is paired with the bitter tastant quinine, has been considered to model some compulsive aspects of human alcohol consumption...
November 2016: Neuropharmacology
Hanna E Kastman, Anna Blasiak, Leigh Walker, Marcin Siwiec, Elena V Krstew, Andrew L Gundlach, Andrew J Lawrence
Alcoholism is a chronic relapsing disorder and a major global health problem. Stress is a key precipitant of relapse in human alcoholics and in animal models of alcohol seeking. The brainstem nucleus incertus (NI) contains a population of relaxin-3 neurons that are highly responsive to psychological stressors; and the ascending NI relaxin-3/RXFP3 signalling system is implicated in stress-induced reinstatement of alcohol seeking. The NI receives orexinergic innervation and expresses orexin1 (OX1) and orexin2 (OX2) receptor mRNA...
November 2016: Neuropharmacology
Bibia Heidmann, John Gatfield, Catherine Roch, Alexander Treiber, Simone Tortoioli, Christine Brotschi, Jodi T Williams, Martin H Bolli, Stefan Abele, Thierry Sifferlen, François Jenck, Christoph Boss
Starting from suvorexant (trade name Belsomra), we successfully identified interesting templates leading to potent dual orexin receptor antagonists (DORAs) via a scaffold-hopping approach. Structure-activity relationship optimization allowed us not only to improve the antagonistic potency on both orexin 1 and orexin 2 receptors (Ox1 and Ox2, respectively), but also to increase metabolic stability in human liver microsomes (HLM), decrease time-dependent inhibition of cytochrome P450 (CYP) 3A4, and decrease P-glycoprotein (Pgp)-mediated efflux...
July 8, 2016: ChemMedChem
Yan Xue, Yu-Ting Yang, Hong-Yun Liu, Wen-Fang Chen, An-Qi Chen, Qing Sheng, Xin-Yi Chen, Ying Wang, Hua Chen, Hong-Xia Liu, Ya-Yan Pang, Lei Chen
Orexin is a member of neuropeptides which was first identified in the hypothalamus. The globus pallidus is a key structure in the basal ganglia, which is involved in both normal motor function and movement disorders. Morphological studies have shown the expression of both OX1 and OX2 receptors in the globus pallidus. Employing single unit extracellular recordings and behavioural tests, the direct in vivo electrophysiological and behavioural effects of orexin-A in the globus pallidus were studied. Micro-pressure administration of orexin-A significantly increased the spontaneous firing rate of pallidal neurons...
September 2016: European Journal of Neuroscience
Maryam Mousavinezhad-Moghaddam, Abbas Ali Amin, Houshang Rafatpanah, Seyed Abdol Rahim Rezaee
The physiologic function of the immune system is defense against infectious microbes and internal tumour cells, Therefore, need to have precise modulatory mechanisms to maintain the body homeostasis. The mammalian cellular CD200 (OX2)/CD200R interaction is one of such modulatory mechanisms in which myeloid and lymphoid cells are regulated. CD200 and CD200R molecules are membrane proteins that their immunomodulatory effects are able to suppress inflammatory responses, particularly in the privilege sites such as CNS and eyes...
January 2016: Iranian Journal of Basic Medical Sciences
Bahman Sadeghi, Somayeh Ezzatpanah, Abbas Haghparast
RATIONALE: Orexinergic system is involved in reward processing and drug addiction. OBJECTIVES: Here, we investigated the effect of intrahippocampal CA1 administration of orexin-2 receptor (OX2r) antagonist on the acquisition, expression, and extinction of morphine-induced place preference in rats. METHODS: Conditioned place preference (CPP) was induced by subcutaneous injection of morphine (5 mg/kg) during a 3-day conditioning phase. Three experimental plots were designed; TCS OX2 29 as a selective antagonist of orexin-2 receptors (OX2rs) was dissolved in DMSO, prepared in solutions with different concentrations (1, 3, 10, and 30 nM), and was bilaterally microinjected into the CA1 and some neighboring regions (0...
June 2016: Psychopharmacology
Shahrnaz Parsania, Marzieh Moradi, Zahra Fatahi, Abbas Haghparast
Orexinergic projections originating from the lateral hypothalamus (LH) have an important role in the acquisition of the LH-stimulation conditioned place preference (CPP). Among the brain areas associated with reward processing, LH orexinergic neurons send projections to the dentate gyrus (DG) region of the hippocampus, and it has been shown that orexin receptors are expressed in the DG. In this study, we investigated the role of intra-DG orexin-1 (OX1) and orexin-2 (OX2) receptors on acquisition, expression and extinction of CPP induced by stimulation of the LH...
May 15, 2016: Brain Research
Jie Yin, Kerim Babaoglu, Chad A Brautigam, Lindsay Clark, Zhenhua Shao, Thomas H Scheuermann, Charles M Harrell, Anthony L Gotter, Anthony J Roecker, Christopher J Winrow, John J Renger, Paul J Coleman, Daniel M Rosenbaum
The orexin (also known as hypocretin) G protein-coupled receptors (GPCRs) regulate sleep and other behavioral functions in mammals, and are therapeutic targets for sleep and wake disorders. The human receptors hOX1R and hOX2R, which are 64% identical in sequence, have overlapping but distinct physiological functions and potential therapeutic profiles. We determined structures of hOX1R bound to the OX1R-selective antagonist SB-674042 and the dual antagonist suvorexant at 2.8-Å and 2.75-Å resolution, respectively, and used molecular modeling to illuminate mechanisms of antagonist subtype selectivity between hOX1R and hOX2R...
April 2016: Nature Structural & Molecular Biology
Li-Na Zhang, Cen Yang, Peng-Rong Ouyang, Zhi-Chao Zhang, Ming-Zi Ran, Li Tong, Hai-Long Dong, Yong Liu
Previous studies have demonstrated that orexinergic neurons involve in promoting emergence from anesthesia of propofol, an intravenous anesthetics, while whether both of orexin-A and orexin-B have promotive action on emergence via mediation of basal forebrain (BF) in isoflurane anesthesia has not been elucidated. In this study, we observed c-Fos expressions in orexinergic neurons following isoflurane inhalation (for 0, 30, 60, and 120min) and at the time when the righting reflex returned after the cessation of anesthesia...
August 2016: Neuropeptides
Katarzyna Socała, Agnieszka Szuster-Ciesielska, Piotr Wlaź
AIM: Orexins A and B are hypothalamic neuropeptides involved in a number of physiological and behavioral processes. They work via OX1 and OX2 receptors. Recent studies revealed that orexins may be implicated in seizure activity. Therefore, the present study was undertaken to evaluate the influence of SB 334867 (a selective OX1 receptor antagonist) and EMPA (a selective OX2 receptor antagonist) on the seizure thresholds in mice. We also aimed to determine the changes of orexin A level following different types of seizures...
April 1, 2016: Life Sciences
Hsin-Jung Lee, Lu-Yang Chang, Yu-Cheng Ho, Shu-Fang Teng, Ling-Ling Hwang, Ken Mackie, Lih-Chu Chiou
The orexin system consists of orexin A/hypocretin 1 and orexin B/hypocretin 2, and OX1 and OX2 receptors. Our previous electrophysiological study showed that orexin A in the rat ventrolateral periaqueductal gray (vlPAG) induced antinociception via an OX1 receptor-initiated and endocannabinoid-mediated disinhibition mechanism. Here, we further characterized antinociceptive effects of orexins in the mouse vlPAG and investigated whether this mechanism in the vlPAG can contribute to stress-induced analgesia (SIA) in mice...
June 2016: Neuropharmacology
Fatemeh Yazdi, Mahboubeh Jahangirvand, Somayeh Ezzatpanah, Abbas Haghparast
Orexins, which are mainly produced by orexin-expressing neurons in the lateral hypothalamus (LH), play an important role in pain modulation. Previously, it has been established that the nucleus accumbens (NAc) is involved in the modulation of formalin-induced nociceptive responses, a model of tonic pain. In this study, the role of intra-accumbal orexin-2 receptors (OX2rs) in the mediation of formalin-induced pain was investigated. A volume of 0.5 μl of 10, 20, and 40 nmol/l solutions of TCS OX2 29, an OX2r antagonist, were unilaterally microinjected into the NAc 5 min before an intra-LH carbachol microinjection (0...
August 2016: Behavioural Pharmacology
S Ezzatpanah, V Babapour, A Haghparast
BACKGROUND: Orexinergic neurons in the lateral hypothalamus (LH) play an important role in pain modulation. In addition, ventral tegmental area (VTA) is known as a part of descending pain modulatory circuitry. Little is known about the interaction between the LH and neural substrates involving in modulation of formalin-induced nociception. Accordingly, we aimed to examine the pain modulatory role of VTA orexin receptors in the formalin test. METHODS: Seventy-eight male Wistar rats were unilaterally implanted with two cannulae above the LH and VTA...
August 2016: European Journal of Pain: EJP
Samir Ghorai, Amrit Sarmah, Ram Kinkar Roy, Archana Tiwari, Chandan Mukherjee
Ligand H3Sami(Mixed(tBu)) was composed of two different compartments, a redox-active 2-aminophenol and a salen salicylidene. Both compartments were linked via a benzyl linker. The ligand reacted with CuCl2·2H2O under air in the presence of Et3N and provided the corresponding monoradical-coordinated mononuclear Cu(II) complex (1). Complex 1, in solution, reacted with air and provided complex 2 via ligand-centered oxygenation at the benzyl-CH2 position. Both complexes were characterized via IR, mass spectrometry, X-ray single-crystal diffraction, variable-temperature magnetic susceptibility, cyclic voltammograms (CVs), and UV-vis/NIR spectroscopic techniques...
February 15, 2016: Inorganic Chemistry
África Flores, Marina Julià-Hernández, Rafael Maldonado, Fernando Berrendero
BACKGROUND AND PURPOSE: Anatomical, biochemical and pharmacological evidence suggest the existence of a crosstalk between the orexinergic and endocannabinoid systems. While the orexin receptor 1 (OX1 receptor) modulates the reinforcing properties of cannabinoids, the participation of orexins in the acute pharmacological effects of Δ(9) -tetrahydrocannabinol (THC) remains unexplored. EXPERIMENTAL APPROACH: We assessed the possible role of orexins in THC-induced hypolocomotion, hypothermia, antinociception, anxiolytic- and anxiogenic-like effects and memory impairment...
April 2016: British Journal of Pharmacology
Fereshte Ebrahimian, Farzaneh Sadat Naghavi, Fatemeh Yazdi, Fatemeh Sadeghzadeh, Zahra Taslimi, Abbas Haghparast
Orexins are hypothalamic peptides involved in the modulation of the feeding, arousal, reward function, learning, and memory; nevertheless, the role of orexins in stress and relapse are largely unclear. Therefore, in the present study, the reinstatement model were used to examine the effects of intradentate gyrus (DG) administration of SB334867 as an orexin-1 receptor antagonist and TCS OX2 29, as an orexin-2 receptor antagonist on drug priming- and forced swim stress (FSS)-induced reinstatement of morphine...
February 2016: Behavioral Neuroscience
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