Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.
Identifieur interne : 001298 ( PubMed/Curation ); précédent : 001297; suivant : 001299Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.
Auteurs : Jennifer R. Deuis [Australie] ; Zoltan Dekan [Australie] ; Joshua S. Wingerd [Australie] ; Jennifer J. Smith [Australie] ; Nehan R. Munasinghe [Australie] ; Rebecca F. Bhola [Australie] ; Wendy L. Imlach [Australie] ; Volker Herzig [Australie] ; David A. Armstrong [Australie] ; K Johan Rosengren [Australie] ; Frank Bosmans [États-Unis] ; Stephen G. Waxman [États-Unis] ; Sulayman D. Dib-Hajj [États-Unis] ; Pierre Escoubas [France] ; Michael S. Minett [Royaume-Uni] ; Macdonald J. Christie [Australie] ; Glenn F. King [Australie] ; Paul F. Alewood [Australie] ; Richard J. Lewis [Australie] ; John N. Wood [Royaume-Uni] ; Irina Vetter [Australie]Source :
- Scientific reports [ 2045-2322 ] ; 2017.
Abstract
Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40-1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective NaV1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective NaV1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted NaV1.7 inhibitors can only produce analgesia when administered in combination with an opioid.
DOI: 10.1038/srep40883
PubMed: 28106092
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Deuis</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Dekan, Zoltan" sort="Dekan, Zoltan" uniqKey="Dekan Z" first="Zoltan" last="Dekan">Zoltan Dekan</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Wingerd, Joshua S" sort="Wingerd, Joshua S" uniqKey="Wingerd J" first="Joshua S" last="Wingerd">Joshua S. 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Smith</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Munasinghe, Nehan R" sort="Munasinghe, Nehan R" uniqKey="Munasinghe N" first="Nehan R" last="Munasinghe">Nehan R. 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Bhola</name><affiliation wicri:level="1"><nlm:affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006</wicri:regionArea></affiliation></author><author><name sortKey="Imlach, Wendy L" sort="Imlach, Wendy L" uniqKey="Imlach W" first="Wendy L" last="Imlach">Wendy L. Imlach</name><affiliation wicri:level="1"><nlm:affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006</wicri:regionArea></affiliation></author><author><name sortKey="Herzig, Volker" sort="Herzig, Volker" uniqKey="Herzig V" first="Volker" last="Herzig">Volker Herzig</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Armstrong, David A" sort="Armstrong, David A" uniqKey="Armstrong D" first="David A" last="Armstrong">David A. Armstrong</name><affiliation wicri:level="1"><nlm:affiliation>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Rosengren, K Johan" sort="Rosengren, K Johan" uniqKey="Rosengren K" first="K Johan" last="Rosengren">K Johan Rosengren</name><affiliation wicri:level="1"><nlm:affiliation>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Bosmans, Frank" sort="Bosmans, Frank" uniqKey="Bosmans F" first="Frank" last="Bosmans">Frank Bosmans</name><affiliation wicri:level="1"><nlm:affiliation>Department of Physiology &Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology &Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205</wicri:regionArea></affiliation></author><author><name sortKey="Waxman, Stephen G" sort="Waxman, Stephen G" uniqKey="Waxman S" first="Stephen G" last="Waxman">Stephen G. Waxman</name><affiliation wicri:level="1"><nlm:affiliation>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516</wicri:regionArea></affiliation></author><author><name sortKey="Dib Hajj, Sulayman D" sort="Dib Hajj, Sulayman D" uniqKey="Dib Hajj S" first="Sulayman D" last="Dib-Hajj">Sulayman D. Dib-Hajj</name><affiliation wicri:level="1"><nlm:affiliation>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516</wicri:regionArea></affiliation></author><author><name sortKey="Escoubas, Pierre" sort="Escoubas, Pierre" uniqKey="Escoubas P" first="Pierre" last="Escoubas">Pierre Escoubas</name><affiliation wicri:level="1"><nlm:affiliation>Venomtech, Sophie-Antipolis, 06560, Valbonne, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Venomtech, Sophie-Antipolis, 06560, Valbonne</wicri:regionArea></affiliation></author><author><name sortKey="Minett, Michael S" sort="Minett, Michael S" uniqKey="Minett M" first="Michael S" last="Minett">Michael S. Minett</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT</wicri:regionArea></affiliation></author><author><name sortKey="Christie, Macdonald J" sort="Christie, Macdonald J" uniqKey="Christie M" first="Macdonald J" last="Christie">Macdonald J. 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Alewood</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Lewis, Richard J" sort="Lewis, Richard J" uniqKey="Lewis R" first="Richard J" last="Lewis">Richard J. Lewis</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Wood, John N" sort="Wood, John N" uniqKey="Wood J" first="John N" last="Wood">John N. Wood</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT</wicri:regionArea></affiliation></author><author><name sortKey="Vetter, Irina" sort="Vetter, Irina" uniqKey="Vetter I" first="Irina" last="Vetter">Irina Vetter</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2017">2017</date><idno type="RBID">pubmed:28106092</idno><idno type="pmid">28106092</idno><idno type="doi">10.1038/srep40883</idno><idno type="wicri:Area/PubMed/Corpus">001320</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">001320</idno><idno type="wicri:Area/PubMed/Curation">001298</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">001298</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.</title><author><name sortKey="Deuis, Jennifer R" sort="Deuis, Jennifer R" uniqKey="Deuis J" first="Jennifer R" last="Deuis">Jennifer R. Deuis</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Dekan, Zoltan" sort="Dekan, Zoltan" uniqKey="Dekan Z" first="Zoltan" last="Dekan">Zoltan Dekan</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Wingerd, Joshua S" sort="Wingerd, Joshua S" uniqKey="Wingerd J" first="Joshua S" last="Wingerd">Joshua S. Wingerd</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Smith, Jennifer J" sort="Smith, Jennifer J" uniqKey="Smith J" first="Jennifer J" last="Smith">Jennifer J. Smith</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Munasinghe, Nehan R" sort="Munasinghe, Nehan R" uniqKey="Munasinghe N" first="Nehan R" last="Munasinghe">Nehan R. Munasinghe</name><affiliation wicri:level="1"><nlm:affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006</wicri:regionArea></affiliation></author><author><name sortKey="Bhola, Rebecca F" sort="Bhola, Rebecca F" uniqKey="Bhola R" first="Rebecca F" last="Bhola">Rebecca F. Bhola</name><affiliation wicri:level="1"><nlm:affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006</wicri:regionArea></affiliation></author><author><name sortKey="Imlach, Wendy L" sort="Imlach, Wendy L" uniqKey="Imlach W" first="Wendy L" last="Imlach">Wendy L. Imlach</name><affiliation wicri:level="1"><nlm:affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006</wicri:regionArea></affiliation></author><author><name sortKey="Herzig, Volker" sort="Herzig, Volker" uniqKey="Herzig V" first="Volker" last="Herzig">Volker Herzig</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Armstrong, David A" sort="Armstrong, David A" uniqKey="Armstrong D" first="David A" last="Armstrong">David A. Armstrong</name><affiliation wicri:level="1"><nlm:affiliation>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Rosengren, K Johan" sort="Rosengren, K Johan" uniqKey="Rosengren K" first="K Johan" last="Rosengren">K Johan Rosengren</name><affiliation wicri:level="1"><nlm:affiliation>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Bosmans, Frank" sort="Bosmans, Frank" uniqKey="Bosmans F" first="Frank" last="Bosmans">Frank Bosmans</name><affiliation wicri:level="1"><nlm:affiliation>Department of Physiology &Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Physiology &Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205</wicri:regionArea></affiliation></author><author><name sortKey="Waxman, Stephen G" sort="Waxman, Stephen G" uniqKey="Waxman S" first="Stephen G" last="Waxman">Stephen G. Waxman</name><affiliation wicri:level="1"><nlm:affiliation>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516</wicri:regionArea></affiliation></author><author><name sortKey="Dib Hajj, Sulayman D" sort="Dib Hajj, Sulayman D" uniqKey="Dib Hajj S" first="Sulayman D" last="Dib-Hajj">Sulayman D. Dib-Hajj</name><affiliation wicri:level="1"><nlm:affiliation>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, USA.</nlm:affiliation><country xml:lang="fr">États-Unis</country><wicri:regionArea>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516</wicri:regionArea></affiliation></author><author><name sortKey="Escoubas, Pierre" sort="Escoubas, Pierre" uniqKey="Escoubas P" first="Pierre" last="Escoubas">Pierre Escoubas</name><affiliation wicri:level="1"><nlm:affiliation>Venomtech, Sophie-Antipolis, 06560, Valbonne, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>Venomtech, Sophie-Antipolis, 06560, Valbonne</wicri:regionArea></affiliation></author><author><name sortKey="Minett, Michael S" sort="Minett, Michael S" uniqKey="Minett M" first="Michael S" last="Minett">Michael S. Minett</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT</wicri:regionArea></affiliation></author><author><name sortKey="Christie, Macdonald J" sort="Christie, Macdonald J" uniqKey="Christie M" first="Macdonald J" last="Christie">Macdonald J. Christie</name><affiliation wicri:level="1"><nlm:affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006</wicri:regionArea></affiliation></author><author><name sortKey="King, Glenn F" sort="King, Glenn F" uniqKey="King G" first="Glenn F" last="King">Glenn F. King</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Alewood, Paul F" sort="Alewood, Paul F" uniqKey="Alewood P" first="Paul F" last="Alewood">Paul F. Alewood</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Lewis, Richard J" sort="Lewis, Richard J" uniqKey="Lewis R" first="Richard J" last="Lewis">Richard J. Lewis</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author><author><name sortKey="Wood, John N" sort="Wood, John N" uniqKey="Wood J" first="John N" last="Wood">John N. Wood</name><affiliation wicri:level="1"><nlm:affiliation>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.</nlm:affiliation><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT</wicri:regionArea></affiliation></author><author><name sortKey="Vetter, Irina" sort="Vetter, Irina" uniqKey="Vetter I" first="Irina" last="Vetter">Irina Vetter</name><affiliation wicri:level="1"><nlm:affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072</wicri:regionArea></affiliation></author></analytic><series><title level="j">Scientific reports</title><idno type="eISSN">2045-2322</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40-1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective NaV1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective NaV1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted NaV1.7 inhibitors can only produce analgesia when administered in combination with an opioid.</div></front></TEI><pubmed><MedlineCitation Status="In-Data-Review" Owner="NLM"><PMID Version="1">28106092</PMID><DateCreated><Year>2017</Year><Month>01</Month><Day>20</Day></DateCreated><DateRevised><Year>2017</Year><Month>08</Month><Day>23</Day></DateRevised><Article PubModel="Electronic"><Journal><ISSN IssnType="Electronic">2045-2322</ISSN><JournalIssue CitedMedium="Internet"><Volume>7</Volume><PubDate><Year>2017</Year><Month>Jan</Month><Day>20</Day></PubDate></JournalIssue><Title>Scientific reports</Title><ISOAbbreviation>Sci Rep</ISOAbbreviation></Journal><ArticleTitle>Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.</ArticleTitle><Pagination><MedlinePgn>40883</MedlinePgn></Pagination><ELocationID EIdType="doi" ValidYN="Y">10.1038/srep40883</ELocationID><Abstract><AbstractText>Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40-1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective NaV1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective NaV1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted NaV1.7 inhibitors can only produce analgesia when administered in combination with an opioid.</AbstractText></Abstract><AuthorList CompleteYN="Y"><Author ValidYN="Y"><LastName>Deuis</LastName><ForeName>Jennifer R</ForeName><Initials>JR</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dekan</LastName><ForeName>Zoltan</ForeName><Initials>Z</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wingerd</LastName><ForeName>Joshua S</ForeName><Initials>JS</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Smith</LastName><ForeName>Jennifer J</ForeName><Initials>JJ</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Munasinghe</LastName><ForeName>Nehan R</ForeName><Initials>NR</Initials><AffiliationInfo><Affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bhola</LastName><ForeName>Rebecca F</ForeName><Initials>RF</Initials><AffiliationInfo><Affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Imlach</LastName><ForeName>Wendy L</ForeName><Initials>WL</Initials><AffiliationInfo><Affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Herzig</LastName><ForeName>Volker</ForeName><Initials>V</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Armstrong</LastName><ForeName>David A</ForeName><Initials>DA</Initials><AffiliationInfo><Affiliation>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Rosengren</LastName><ForeName>K Johan</ForeName><Initials>KJ</Initials><AffiliationInfo><Affiliation>School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Bosmans</LastName><ForeName>Frank</ForeName><Initials>F</Initials><AffiliationInfo><Affiliation>Department of Physiology &Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Waxman</LastName><ForeName>Stephen G</ForeName><Initials>SG</Initials><AffiliationInfo><Affiliation>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Dib-Hajj</LastName><ForeName>Sulayman D</ForeName><Initials>SD</Initials><AffiliationInfo><Affiliation>Department of Neurology and Center for Neuroscience and Regeneration Research, Yale University School of Medicine, New Haven, Connecticut 06510, Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516, USA.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Escoubas</LastName><ForeName>Pierre</ForeName><Initials>P</Initials><AffiliationInfo><Affiliation>Venomtech, Sophie-Antipolis, 06560, Valbonne, France.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Minett</LastName><ForeName>Michael S</ForeName><Initials>MS</Initials><AffiliationInfo><Affiliation>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Christie</LastName><ForeName>Macdonald J</ForeName><Initials>MJ</Initials><AffiliationInfo><Affiliation>Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>King</LastName><ForeName>Glenn F</ForeName><Initials>GF</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Alewood</LastName><ForeName>Paul F</ForeName><Initials>PF</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Lewis</LastName><ForeName>Richard J</ForeName><Initials>RJ</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Wood</LastName><ForeName>John N</ForeName><Initials>JN</Initials><AffiliationInfo><Affiliation>Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.</Affiliation></AffiliationInfo></Author><Author ValidYN="Y"><LastName>Vetter</LastName><ForeName>Irina</ForeName><Initials>I</Initials><AffiliationInfo><Affiliation>IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.</Affiliation></AffiliationInfo><AffiliationInfo><Affiliation>School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, 20 Cornwall St, Woolloongabba, Queensland, 4102, Australia.</Affiliation></AffiliationInfo></Author></AuthorList><Language>eng</Language><GrantList CompleteYN="Y"><Grant><GrantID>UL1 TR001863</GrantID><Acronym>TR</Acronym><Agency>NCATS NIH HHS</Agency><Country>United States</Country></Grant></GrantList><PublicationTypeList><PublicationType UI="D016428">Journal 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