title: Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain.
abstract: 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.
authors.affiliation: Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. j.deuis@uq.edu.au.|School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia. j.deuis@uq.edu.au.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Deuis
authors.affiliation: Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. j.wingerd@imb.uq.edu.au.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Wingerd
authors.affiliation: Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. zoltan.winter@kfa.imed.uni-erlangen.de.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Winter
authors.affiliation: Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. t.durek@imb.uq.edu.au.
authors.forename: Thomas
authors.initials: T
authors.lastname: Durek
authors.affiliation: Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. z.dekan@imb.uq.edu.au.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Dekan
authors.affiliation: Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. s.desousa@imb.uq.edu.au.
authors.forename: Silmara R
authors.initials: SR
authors.lastname: Sousa
authors.affiliation: Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. katharina.zimmermann@fau.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Zimmermann
authors.affiliation: Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. tal.hoffmann@fau.de.
authors.forename: Tali
authors.initials: T
authors.lastname: Hoffmann
authors.affiliation: Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. Weidner@physiologie1.uni-erlangen.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Weidner
authors.affiliation: Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK. m.nassar@sheffield.ac.uk.
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Nassar
authors.affiliation: Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. p.alewood@imb.uq.edu.au.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
authors.affiliation: Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. r.lewis@uq.edu.au.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.affiliation: Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. i.vetter@uq.edu.au.|School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia. i.vetter@uq.edu.au.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
mesh_terms: D000700:Analgesics; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D016466:CHO Cells; D003412:Cricetulus; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008810:Mice, Inbred C57BL; D062556:NAV1.7 Voltage-Gated Sodium Channel / Q000235:genetics / Q000502:physiology*; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy*; D010455:Peptides / Q000627:therapeutic use*; D010647:Phenyl Ethers / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives* / Q000627:therapeutic use; D012501:Saphenous Vein / Q000294:innervation; D012604:Scorpion Venoms / Q000627:therapeutic use*; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D013111:Spider Venoms / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use
chemical_list: D000700:Analgesics; C000609915:GpTx-1 protein, Grammostola porteri; D062556:NAV1.7 Voltage-Gated Sodium Channel; C514165:OD1 toxin, Odonthobuthus doriae; D010455:Peptides; D010647:Phenyl Ethers; D012604:Scorpion Venoms; D026941:Sodium Channel Blockers; D013111:Spider Venoms; D013449:Sulfonamides; D011392:Proline; C000592131:vixotrigine
keywords: CNV1014802; GpTx-1; NaV1.7; OD1; PF-04856264; pain; raxatrigine