title: Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.
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 (IC500.9 nM) with at least 40-1000-fold selectivity over all other NaVsubtypes. 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.
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Deuis
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Dekan
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Wingerd
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Smith
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Nehan R
authors.initials: NR
authors.lastname: Munasinghe
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Rebecca F
authors.initials: RF
authors.lastname: Bhola
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Imlach
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Volker
authors.initials: V
authors.lastname: Herzig
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Armstrong
authors.affiliation: School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: K Johan
authors.initials: KJ
authors.lastname: Rosengren
authors.affiliation: Department of Physiology &Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Frank
authors.initials: F
authors.lastname: Bosmans
authors.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.
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.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.
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.affiliation: Venomtech, Sophie-Antipolis, 06560, Valbonne, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Escoubas
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Minett
authors.affiliation: Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.
authors.forename: Macdonald J
authors.initials: MJ
authors.lastname: Christie
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Glenn F
authors.initials: GF
authors.lastname: King
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Alewood
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.affiliation: IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.|School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, 20 Cornwall St, Woolloongabba, Queensland, 4102, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter