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Sci Rep. 2017 Jan 20;7:40883. doi: 10.1038/srep40883.

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.

Author information

1
IMB Centre for Pain Research, Institute for Molecular Bioscience, 306 Carmody Rd (Building 80), The University of Queensland, St Lucia, Queensland, 4072, Australia.
2
Discipline of Pharmacology, School of Medical Sciences, The University of Sydney, Sydney, New South Wales, 2006, Australia.
3
School of Biomedical Sciences, The University of Queensland, St Lucia, Queensland, 4072, Australia.
4
Department of Physiology &Solomon H. Snyder Department of Neuroscience, Johns Hopkins University, School of Medicine, Baltimore, MD 21205, USA.
5
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.
6
Venomtech, Sophie-Antipolis, 06560, Valbonne, France.
7
Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
8
School of Pharmacy, The University of Queensland, Pharmacy Australia Centre of Excellence, 20 Cornwall St, Woolloongabba, Queensland, 4102, Australia.

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.

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