Pharmacological characterisation of the highly Nav1.7 selective spider venom peptide Pn3a

Deuis, Jennifer R., Dekan, Zoltan, Wingerd, Joshua S., Smith, Jennifer J., Munasinghe, Nehan R., Bhola, Rebecca F., Imlach, Wendy L., Herzig, Volker, Armstrong, David A., Rosengren, K. Johan, Bosmans, Frank, Waxman, Stephen G., Dib-Hajj, Sulayman D., Escoubas, Pierre, Minett, Michael S., Christie, Macdonald J., King, Glenn F., Alewood, Paul F., Lewis, Richard J., Wood, John N. and Vetter, Irina (2017) Pharmacological characterisation of the highly Nav1.7 selective spider venom peptide Pn3a. Scientific Reports, 7 . doi:10.1038/srep40883


Author Deuis, Jennifer R.
Dekan, Zoltan
Wingerd, Joshua S.
Smith, Jennifer J.
Munasinghe, Nehan R.
Bhola, Rebecca F.
Imlach, Wendy L.
Herzig, Volker
Armstrong, David A.
Rosengren, K. Johan
Bosmans, Frank
Waxman, Stephen G.
Dib-Hajj, Sulayman D.
Escoubas, Pierre
Minett, Michael S.
Christie, Macdonald J.
King, Glenn F.
Alewood, Paul F.
Lewis, Richard J.
Wood, John N.
Vetter, Irina
Title Pharmacological characterisation of the highly Nav1.7 selective spider venom peptide Pn3a
Formatted title
Pharmacological characterisation of the highly Nav1.7 selective spider venom peptide Pn3a
Journal name Scientific Reports   Check publisher's open access policy
ISSN 2045-2322
Publication date 2017-01-20
Sub-type Article (original research)
DOI 10.1038/srep40883
Open Access Status DOI
Volume 7
Total pages 18
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Formatted 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 (IC 50 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.
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

 
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