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Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain.
Deuis, Jennifer R; Wingerd, Joshua S; Winter, Zoltan; Durek, Thomas; Dekan, Zoltan; Sousa, Silmara R; Zimmermann, Katharina; Hoffmann, Tali; Weidner, Christian; Nassar, Mohammed A; Alewood, Paul F; Lewis, Richard J; Vetter, Irina.
Afiliación
  • Deuis JR; Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. j.deuis@uq.edu.au.
  • Wingerd JS; School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia. j.deuis@uq.edu.au.
  • Winter Z; Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. j.wingerd@imb.uq.edu.au.
  • Durek T; Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. zoltan.winter@kfa.imed.uni-erlangen.de.
  • Dekan Z; Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. t.durek@imb.uq.edu.au.
  • Sousa SR; Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. z.dekan@imb.uq.edu.au.
  • Zimmermann K; Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. s.desousa@imb.uq.edu.au.
  • Hoffmann T; Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. katharina.zimmermann@fau.de.
  • Weidner C; Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. tal.hoffmann@fau.de.
  • Nassar MA; Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. Weidner@physiologie1.uni-erlangen.de.
  • Alewood PF; Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK. m.nassar@sheffield.ac.uk.
  • Lewis RJ; Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. p.alewood@imb.uq.edu.au.
  • Vetter I; Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. r.lewis@uq.edu.au.
Toxins (Basel) ; 8(3)2016 Mar 17.
Article en En | MEDLINE | ID: mdl-26999206
Loss-of-function mutations of Na(V)1.7 lead to congenital insensitivity to pain, a rare condition resulting in individuals who are otherwise normal except for the inability to sense pain, making pharmacological inhibition of Na(V)1.7 a promising therapeutic strategy for the treatment of pain. We characterized a novel mouse model of Na(V)1.7-mediated pain based on intraplantar injection of the scorpion toxin OD1, which is suitable for rapid in vivo profiling of Na(V)1.7 inhibitors. Intraplantar injection of OD1 caused spontaneous pain behaviors, which were reversed by co-injection with Na(V)1.7 inhibitors and significantly reduced in Na(V)1.7(-/-) mice. To validate the use of the model for profiling Na(V)1.7 inhibitors, we determined the Na(V) selectivity and tested the efficacy of the reported Na(V)1.7 inhibitors GpTx-1, PF-04856264 and CNV1014802 (raxatrigine). GpTx-1 selectively inhibited Na(V)1.7 and was effective when co-administered with OD1, but lacked efficacy when delivered systemically. PF-04856264 state-dependently and selectively inhibited Na(V)1.7 and significantly reduced OD1-induced spontaneous pain when delivered locally and systemically. CNV1014802 state-dependently, but non-selectively, inhibited Na(V) channels and was only effective in the OD1 model when delivered systemically. Our novel model of Na(V)1.7-mediated pain based on intraplantar injection of OD1 is thus suitable for the rapid in vivo characterization of the analgesic efficacy of Na(V)1.7 inhibitors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dolor / Péptidos / Éteres Fenílicos / Venenos de Escorpión / Venenos de Araña / Prolina / Bloqueadores de los Canales de Sodio / Canal de Sodio Activado por Voltaje NAV1.7 Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Toxins (Basel) Año: 2016 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Suiza
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Dolor / Péptidos / Éteres Fenílicos / Venenos de Escorpión / Venenos de Araña / Prolina / Bloqueadores de los Canales de Sodio / Canal de Sodio Activado por Voltaje NAV1.7 Tipo de estudio: Prognostic_studies Límite: Animals / Humans / Male Idioma: En Revista: Toxins (Basel) Año: 2016 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Suiza