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      Potassium Channels in Peripheral Pain Pathways: Expression, Function and Therapeutic Potential

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          Abstract

          Electrical excitation of peripheral somatosensory nerves is a first step in generation of most pain signals in mammalian nervous system. Such excitation is controlled by an intricate set of ion channels that are coordinated to produce a degree of excitation that is proportional to the strength of the external stimulation. However, in many disease states this coordination is disrupted resulting in deregulated peripheral excitability which, in turn, may underpin pathological pain states (i.e. migraine, neuralgia, neuropathic and inflammatory pains). One of the major groups of ion channels that are essential for controlling neuronal excitability is potassium channel family and, hereby, the focus of this review is on the K+ channels in peripheral pain pathways. The aim of the review is threefold. First, we will discuss current evidence for the expression and functional role of various K+ channels in peripheral nociceptive fibres. Second, we will consider a hypothesis suggesting that reduced functional activity of K+ channels within peripheral nociceptive pathways is a general feature of many types of pain. Third, we will evaluate the perspectives of pharmacological enhancement of K+ channels in nociceptive pathways as a strategy for new analgesic drug design.

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          A TRP channel that senses cold stimuli and menthol.

          A distinct subset of sensory neurons are thought to directly sense changes in thermal energy through their termini in the skin. Very little is known about the molecules that mediate thermoreception by these neurons. Vanilloid Receptor 1 (VR1), a member of the TRP family of channels, is activated by noxious heat. Here we describe the cloning and characterization of TRPM8, a distant relative of VR1. TRPM8 is specifically expressed in a subset of pain- and temperature-sensing neurons. Cells overexpressing the TRPM8 channel can be activated by cold temperatures and by a cooling agent, menthol. Our identification of a cold-sensing TRP channel in a distinct subpopulation of sensory neurons implicates an expanded role for this family of ion channels in somatic sensory detection.
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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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              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

                Journal
                Curr Neuropharmacol
                Curr Neuropharmacol
                cn
                Current Neuropharmacology
                Bentham Science Publishers
                1570-159X
                1875-6190
                December 2013
                December 2013
                : 11
                : 6
                : 621-640
                Affiliations
                [1 ]Department of Pharmacology, Hebei Medical University, Shijiazhuang, China;
                [2 ]Faculty of Biological Sciences, University of Leeds, Leeds, UK
                Author notes
                [* ]Address correspondence to these authors at the School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, LS2 9JT, Tel: +44 113 343 7923; E-mail: n.gamper@leeds.ac.uk and Hebei Medical University, 361 East Zhongshan Road, Shijiazhuang, Hebei Province, 050017, P.R. China; Tel: +86 31186266073; E-mail: du_xiaona@ 123456hotmail.com
                Article
                CN-11-621
                10.2174/1570159X113119990042
                3849788
                24396338
                a4e9fd87-bab4-48c7-a690-57b3f40523dd
                ©2013 Bentham Science Publishers

                This is an open access article licensed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided the work is properly cited.

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                Categories
                Article

                Pharmacology & Pharmaceutical medicine
                k+ channel, m channel, two-pore k+ channel, katp channel, dorsal root ganglion, pain, nociception.

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