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Pharmacological characterisation of the highly Na v 1.7 selective spider venom peptide Pn3a
Journal article   Open access   Peer reviewed

Pharmacological characterisation of the highly Na v 1.7 selective spider venom peptide Pn3a

J R Deuis, Z Dekan, J S Wingerd, J J Smith, N R Munasinghe, R F Bhola, W L Imlach, Volker Herzig, D A Armstrong, K J Rosengren, …
Scientific Reports, Vol.7, 40883
2017
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https://doi.org/10.1038/srep40883View
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https://doi.org/10.1038/srep46816View
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Abstract

Human genetic studies have implicated the voltage-gated sodium channel Na V 1.7 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 Na V 1.7 (IC 50 0.9 nM) with at least 40-1000-fold selectivity over all other Na V subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by Na V 1.7 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 Na V 1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective Na V 1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted Na V 1.7 inhibitors can only produce analgesia when administered in combination with an opioid. © The Author(s) 2017.

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