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      Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

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          Abstract

          Chronic pain is a common detrimental condition that affects around 20% of the world population. The current drugs to treat chronic pain states, especially neuropathic pain, have a limited clinical efficiency and present significant adverse effects that complicates their regular use. Recent studies have proposed new therapeutic strategies focused on the pharmacological modulation of G-protein-coupled receptors, transporters, enzymes, and ion channels expressed on the nociceptive pathways. The present work intends to summarize recent advances on the pharmacological modulation of pentameric ligand-gated ion channels, which plays a key role in pain processing. Experimental data have shown that novel allosteric modulators targeting the excitatory nicotinic acetylcholine receptor, as well as the inhibitory GABA A and glycine receptors, reverse chronic pain-related behaviors in preclinical assays. Collectively, these evidences strongly suggest the pharmacological modulation of pentameric ligand-gated ion channels is a promising strategy towards the development of novel therapeutics to treat chronic pain states in humans.

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          Most cited references67

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          Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system.

          Nicotinic receptors - a family of ligand-gated ion channels that mediate the effects of the neurotransmitter acetylcholine - are among the most well understood allosteric membrane proteins from a structural and functional perspective. There is also considerable interest in modulating nicotinic receptors to treat nervous-system disorders such as Alzheimer's disease, schizophrenia, depression, attention deficit hyperactivity disorder and tobacco addiction. This article describes both recent advances in our understanding of the assembly, activity and conformational transitions of nicotinic receptors, as well as developments in the therapeutic application of nicotinic receptor ligands, with the aim of aiding novel drug discovery by bridging the gap between these two rapidly developing fields.
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            Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes.

            GABA(A) (gamma-aminobutyric acid(A)) receptors are molecular substrates for the regulation of vigilance, anxiety, muscle tension, epileptogenic activity and memory functions, which is evident from the spectrum of actions elicited by clinically effective drugs acting at their modulatory benzodiazepine-binding site. Here we show, by introducing a histidine-to-arginine point mutation at position 101 of the murine alpha1-subunit gene, that alpha1-type GABA(A) receptors, which are mainly expressed in cortical areas and thalamus, are rendered insensitive to allosteric modulation by benzodiazepine-site ligands, whilst regulation by the physiological neurotransmitter gamma-aminobutyric acid is preserved. alpha1(H101R) mice failed to show the sedative, amnesic and partly the anticonvulsant action of diazepam. In contrast, the anxiolytic-like, myorelaxant, motor-impairing and ethanol-potentiating effects were fully retained, and are attributed to the nonmutated GABA(A) receptors found in the limbic system (alpha2, alpha5), in monoaminergic neurons (alpha3) and in motoneurons (alpha2, alpha5). Thus, benzodiazepine-induced behavioural responses are mediated by specific GABA(A) receptor subtypes in distinct neuronal circuits, which is of interest for drug design.
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              Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.

              Inhibitory neurotransmission in the brain is largely mediated by GABA(A) receptors. Potentiation of GABA receptor activation through an allosteric benzodiazepine (BZ) site produces the sedative, anxiolytic, muscle relaxant, anticonvulsant and cognition-impairing effects of clinically used BZs such as diazepam. We created genetically modified mice (alpha1 H101R) with a diazepam-insensitive alpha1 subtype and a selective BZ site ligand, L-838,417, to explore GABA(A) receptor subtypes mediating specific physiological effects. These two complimentary approaches revealed that the alpha1 subtype mediated the sedative, but not the anxiolytic effects of benzodiazepines. This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                03 March 2020
                2020
                : 11
                : 167
                Affiliations
                [1] 1 Department of Physiology, Faculty of Biological Sciences, University of Concepcion , Concepcion, Chile
                [2] 2 Department of Biomedical Sciences, Faculty of Health Sciences, University of Talca , Talca, Chile
                Author notes

                Edited by: Ashok Kumar, University of Florida, United States

                Reviewed by: Vinod Tiwari, Indian Institute of Technology (BHU), India; Petra Scholze, Medical University of Vienna, Austria; Antoine Taly, Centre National de la Recherche Scientifique (CNRS), France

                *Correspondence: Mónica A. Carrasco, mocarrasco@ 123456utalca.cl ; Gonzalo E. Yévenes, gyevenes@ 123456udec.cl

                This article was submitted to Neuropharmacology, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2020.00167
                7079299
                32218730
                87b20ed8-ce51-4a71-b63d-84dcc8847aad
                Copyright © 2020 Lara, Burgos, Moraga-Cid, Carrasco and Yévenes

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 18 October 2019
                : 07 February 2020
                Page count
                Figures: 1, Tables: 1, Equations: 0, References: 77, Pages: 8, Words: 3988
                Funding
                Funded by: Fondo Nacional de Desarrollo Científico y Tecnológico 10.13039/501100002850
                Categories
                Pharmacology
                Mini Review

                Pharmacology & Pharmaceutical medicine
                pentameric ligand-gated ion channels,chronic pain,allosteric modulation,analgesia,drug development, preclinical research

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