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      M‐type K + channels in peripheral nociceptive pathways

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          Abstract

          Pathological pain is a hyperexcitability disorder. Since the excitability of a neuron is set and controlled by a complement of ion channels it expresses, in order to understand and treat pain, we need to develop a mechanistic insight into the key ion channels controlling excitability within the mammalian pain pathways and how these ion channels are regulated and modulated in various physiological and pathophysiological settings. In this review, we will discuss the emerging data on the expression in pain pathways, functional role and modulation of a family of voltage‐gated K + channels called ‘M channels’ (KCNQ, K v7). M channels are increasingly recognized as important players in controlling pain signalling, especially within the peripheral somatosensory system. We will also discuss the therapeutic potential of M channels as analgesic drug targets.

          Linked Articles

          This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc/

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          Most cited references126

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          Mechanisms of neuropathic pain.

          Neuropathic pain refers to pain that originates from pathology of the nervous system. Diabetes, infection (herpes zoster), nerve compression, nerve trauma, "channelopathies," and autoimmune disease are examples of diseases that may cause neuropathic pain. The development of both animal models and newer pharmacological strategies has led to an explosion of interest in the underlying mechanisms. Neuropathic pain reflects both peripheral and central sensitization mechanisms. Abnormal signals arise not only from injured axons but also from the intact nociceptors that share the innervation territory of the injured nerve. This review focuses on how both human studies and animal models are helping to elucidate the mechanisms underlying these surprisingly common disorders. The rapid gain in knowledge about abnormal signaling promises breakthroughs in the treatment of these often debilitating disorders.
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            Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin.

            Six members of the mammalian transient receptor potential (TRP) ion channels respond to varied temperature thresholds. The natural compounds capsaicin and menthol activate noxious heat-sensitive TRPV1 and cold-sensitive TRPM8, respectively. The burning and cooling perception of capsaicin and menthol demonstrate that these ion channels mediate thermosensation. We show that, in addition to noxious cold, pungent natural compounds present in cinnamon oil, wintergreen oil, clove oil, mustard oil, and ginger all activate TRPA1 (ANKTM1). Bradykinin, an inflammatory peptide acting through its G protein-coupled receptor, also activates TRPA1. We further show that phospholipase C is an important signaling component for TRPA1 activation. Cinnamaldehyde, the most specific TRPA1 activator, excites a subset of sensory neurons highly enriched in cold-sensitive neurons and elicits nociceptive behavior in mice. Collectively, these data demonstrate that TRPA1 activation elicits a painful sensation and provide a potential molecular model for why noxious cold can paradoxically be perceived as burning pain.
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              Chronic inflammation: importance of NOD2 and NALP3 in interleukin-1beta generation.

              Inflammation is part of the non-specific immune response that occurs in reaction to any type of bodily injury. In some disorders, the inflammatory process - which under normal conditions is self-limiting - becomes continuous and chronic inflammatory diseases might develop subsequently. Pattern recognition molecules (PRMs) represent a diverse collection of molecules responsible for sensing danger signals, and together with other immune components they are involved in the first line of defence. NALP3 and NOD2, which belong to a cytosolic subgroup of PRMs, dubbed Nod-like-receptors (NLRs), have been associated recently with inflammatory diseases, specifically Crohn's disease and Blau syndrome (NOD2) and familial cold autoinflammatory syndrome, Muckle-Wells syndrome and chronic infantile neurological cutaneous and articular syndrome (NALP3). The exact effects of the defective proteins are not fully understood, but activation of nuclear factor (NF)-kappaB, transcription, production and secretion of interleukin (IL)-1beta and activation of the inflammasome are some of the processes that might hold clues, and the present review will provide a thorough update in this area.
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                Author and article information

                Contributors
                n.gamper@leeds.ac.uk
                Journal
                Br J Pharmacol
                Br. J. Pharmacol
                10.1111/(ISSN)1476-5381
                BPH
                British Journal of Pharmacology
                John Wiley and Sons Inc. (Hoboken )
                0007-1188
                1476-5381
                17 September 2017
                June 2018
                17 September 2017
                : 175
                : 12 , Themed Section: Recent Advances in Targeting Ion Channels to Treat Chronic Pain. Guest Editors: Edward B Stevens and Gary J Stephens ( doiID: 10.1111/bph.v175.12 )
                : 2158-2172
                Affiliations
                [ 1 ] Department of Pharmacology, The Key Laboratory of Neural and Vascular Biology, Ministry of Education Hebei Medical University Shijiazhuang China
                [ 2 ] The Key Laboratory of New Drug Pharmacology and Toxicology Shijiazhuang Hebei Province China
                [ 3 ] School of Biomedical Sciences, Faculty of Biological Sciences University of Leeds Leeds UK
                [ 4 ] Department of Biology, UTSA Neurosciences Institute University of Texas at San Antonio San Antonio TX USA
                Author notes
                [*] [* ] Correspondence

                Professor Nikita Gamper, School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK.

                E‐mail: n.gamper@ 123456leeds.ac.uk

                Author information
                http://orcid.org/0000-0002-9305-9508
                http://orcid.org/0000-0001-5806-0207
                Article
                BPH13978 2017-BJP-0258-RCT-G.R2
                10.1111/bph.13978
                5980636
                28800673
                94534adb-c1ab-4c41-9648-cbbfd41c7a6a
                © 2017 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 22 February 2017
                : 17 July 2017
                : 03 August 2017
                Page count
                Figures: 4, Tables: 0, Pages: 15, Words: 7771
                Funding
                Funded by: Medical Research Council
                Award ID: MR/K021303/1
                Funded by: National Basic Research Program
                Award ID: 2013CB531302
                Funded by: Key Basic Research Project of Applied Basic Research Program of Hebei Province
                Award ID: 16967712D
                Funded by: National Natural Science Foundation of China
                Award ID: 31270882
                Award ID: 31571088
                Award ID: 81201642
                Funded by: MRC
                Award ID: MR/K021303/1
                Categories
                Review Article
                Themed Section: Review Articles
                Custom metadata
                2.0
                bph13978
                June 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.0 mode:remove_FC converted:31.05.2018

                Pharmacology & Pharmaceutical medicine
                Pharmacology & Pharmaceutical medicine

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