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      Na v1.7 and other voltage-gated sodium channels as drug targets for pain relief

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          ABSTRACT

          Introduction: Chronic pain is a massive clinical problem. We discuss the potential of subtype selective sodium channel blockers that may provide analgesia with limited side effects.

          Areas covered: Sodium channel subtypes have been linked to human pain syndromes through genetic studies. Gain of function mutations in Na v1.7, 1.8 and 1.9 can cause pain, whilst loss of function Na v1.7 mutations lead to loss of pain in otherwise normal people. Intriguingly, both human and mouse Na v1.7 null mutants have increased opioid drive, because naloxone, an opioid antagonist, can reverse the analgesia associated with the loss of Na v1.7 expression.

          Expert Opinion: We believe there is a great future for sodium channel antagonists, particularly Na v1.7 antagonists in treating most pain syndromes. This review deals with recent attempts to develop specific sodium channel blockers, the mechanisms that underpin the Na v1.7 null pain-free phenotype and new routes to analgesia using, for example, gene therapy or combination therapy with subtype specific sodium channel blockers and opioids. The use of selective Na v1.7 antagonists together with either enkephalinase inhibitors or low dose opioids has the potential for side effect-free analgesia, as well as an important opioid sparing function that may be clinically very significant.

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          Most cited references75

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          The Na(V)1.7 sodium channel: from molecule to man.

          The voltage-gated sodium channel Na(V)1.7 is preferentially expressed in peripheral somatic and visceral sensory neurons, olfactory sensory neurons and sympathetic ganglion neurons. Na(V)1.7 accumulates at nerve fibre endings and amplifies small subthreshold depolarizations, poising it to act as a threshold channel that regulates excitability. Genetic and functional studies have added to the evidence that Na(V)1.7 is a major contributor to pain signalling in humans, and homology modelling based on crystal structures of ion channels suggests an atomic-level structural basis for the altered gating of mutant Na(V)1.7 that causes pain.
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            The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways.

            Many damage-sensing neurons express tetrodotoxin (TTX)-resistant voltage-gated sodium channels. Here we examined the role of the sensory-neuron-specific (SNS) TTX-resistant sodium channel alpha subunit in nociception and pain by constructing sns-null mutant mice. These mice expressed only TTX-sensitive sodium currents on step depolarizations from normal resting potentials, showing that all slow TTX-resistant currents are encoded by the sns gene. Null mutants were viable, fertile and apparently normal, although lowered thresholds of electrical activation of C-fibers and increased current densities of TTX-sensitive channels demonstrated compensatory upregulation of TTX-sensitive currents in sensory neurons. Behavioral studies demonstrated a pronounced analgesia to noxious mechanical stimuli, small deficits in noxious thermoreception and delayed development of inflammatory hyperalgesia. These data show that SNS is involved in pain pathways and suggest that blockade of SNS expression or function may produce analgesia without side effects.
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              The cell and molecular basis of mechanical, cold, and inflammatory pain.

              Peripheral pain pathways are activated by a range of stimuli. We used diphtheria toxin to kill all mouse postmitotic sensory neurons expressing the sodium channel Nav1.8. Mice showed normal motor activity and low-threshold mechanical and acute noxious heat responses but did not respond to noxious mechanical pressure or cold. They also showed a loss of enhanced pain responses and spontaneous pain behavior upon treatment with inflammatory insults. In contrast, nerve injury led to heightened pain sensitivity to thermal and mechanical stimuli indistinguishable from that seen with normal littermates. Pain behavior correlates well with central input from sensory neurons measured electrophysiologically in vivo. These data demonstrate that Na(v)1.8-expressing neurons are essential for mechanical, cold, and inflammatory pain but not for neuropathic pain or heat sensing.
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                Author and article information

                Journal
                Expert Opin Ther Targets
                Expert Opin. Ther. Targets
                IETT
                iett20
                Expert Opinion on Therapeutic Targets
                Taylor & Francis
                1472-8222
                1744-7631
                2 August 2016
                12 April 2016
                : 20
                : 8
                : 975-983
                Affiliations
                [ a ]Molecular Nociception Group, Department of Medicine, WIBR, University College London , London WC1E 6BT, UK
                Author notes
                CONTACT John N Wood J.Wood@ 123456ucl.ac.uk Molecular Nociception Group, Department of Medicine, WIBR, University College London , Gower Street, London WC1E 6BT, UK

                Edward C Emery, Ana Paula Luiz and John N Wood contributed equally to this work.

                Article
                1162295
                10.1517/14728222.2016.1162295
                4950419
                26941184
                60dd246b-7edb-481d-a786-542190fcfdc3
                © 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 3 December 2015
                : 2 March 2016
                Page count
                Figures: 1, Tables: 2, References: 84, Pages: 9
                Funding
                Funded by: Medical Research Council 10.13039/501100000265
                Award ID: G0901905
                Funded by: Wellcome Trust
                Award ID: 101054/z/13/z
                Categories
                Review
                Review

                scn9a,nav1.7,sensory neurons,pain,opioids
                scn9a, nav1.7, sensory neurons, pain, opioids

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