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

Jennifer R. Deuis, Zoltan Dekan, Joshua S. Wingerd, Jennifer J. Smith, Nehan R. Munasinghe, Rebecca F. Bhola, Wendy L. Imlach, Volker Herzig, David A. Armstrong, K. Johan Rosengren, Frank Bosmans, Stephen G. Waxman, Sulayman D. Dib-Hajj, Pierre Escoubas, Michael S. Minett, Macdonald J. Christie, Glenn F. King, Paul F. Alewood, Richard J. Lewis, John N. WoodIrina Vetter

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number40883
JournalScientific Reports
Volume7
DOIs
StatePublished - Jan 20 2017

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Spider Venoms
Pharmacology
Pain
Analgesia
Peptides
Opioid Analgesics
Analgesics
Thiorphan
Voltage-Gated Sodium Channels
Neprilysin
Carrageenan
Medical Genetics
Spinal Ganglia
Formaldehyde
Rodentia
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Deuis, J. R., Dekan, Z., Wingerd, J. S., Smith, J. J., Munasinghe, N. R., Bhola, R. F., ... Vetter, I. (2017). Pharmacological characterisation of the highly Na v 1.7 selective spider venom peptide Pn3a. Scientific Reports, 7, [40883]. https://doi.org/10.1038/srep40883

Pharmacological characterisation of the highly Na v 1.7 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.; Vetter, Irina.

In: Scientific Reports, Vol. 7, 40883, 20.01.2017.

Research output: Contribution to journalArticle

Deuis, JR, Dekan, Z, Wingerd, JS, Smith, JJ, Munasinghe, NR, Bhola, RF, Imlach, WL, Herzig, V, Armstrong, DA, Rosengren, KJ, Bosmans, F, Waxman, SG, Dib-Hajj, SD, Escoubas, P, Minett, MS, Christie, MJ, King, GF, Alewood, PF, Lewis, RJ, Wood, JN & Vetter, I 2017, 'Pharmacological characterisation of the highly Na v 1.7 selective spider venom peptide Pn3a', Scientific Reports, vol. 7, 40883. https://doi.org/10.1038/srep40883
Deuis JR, Dekan Z, Wingerd JS, Smith JJ, Munasinghe NR, Bhola RF et al. Pharmacological characterisation of the highly Na v 1.7 selective spider venom peptide Pn3a. Scientific Reports. 2017 Jan 20;7. 40883. https://doi.org/10.1038/srep40883
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. / Pharmacological characterisation of the highly Na v 1.7 selective spider venom peptide Pn3a. In: Scientific Reports. 2017 ; Vol. 7.
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