Analgesic effects of GpTx-1, PF-04856264 and CNV1014802 in a mouse model of NaV1.7-Mediated pain

Deuis, Jennifer R., Wingerd, Joshua S., Winter, Zoltan, Durek, Thomas, Dekan, Zoltan, Sousa, Silmara R., Zimmermann, Katharina, Hoffmann, Tali, Weidner, Christian, Nassar, Mohammed A., Alewood, Paul F., Lewis, Richard J. and Vetter, Irina (2016) Analgesic effects of GpTx-1, PF-04856264 and CNV1014802 in a mouse model of NaV1.7-Mediated pain. Toxins, 8 3: . doi:10.3390/toxins8030078


Author Deuis, Jennifer R.
Wingerd, Joshua S.
Winter, Zoltan
Durek, Thomas
Dekan, Zoltan
Sousa, Silmara R.
Zimmermann, Katharina
Hoffmann, Tali
Weidner, Christian
Nassar, Mohammed A.
Alewood, Paul F.
Lewis, Richard J.
Vetter, Irina
Title Analgesic effects of GpTx-1, PF-04856264 and CNV1014802 in a mouse model of NaV1.7-Mediated pain
Formatted title
Analgesic effects of GpTx-1, PF-04856264 and CNV1014802 in a mouse model of NaV1.7-Mediated pain
Journal name Toxins   Check publisher's open access policy
ISSN 2072-6651
Publication date 2016-03-17
Year available 2016
Sub-type Article (original research)
DOI 10.3390/toxins8030078
Open Access Status DOI
Volume 8
Issue 3
Total pages 19
Place of publication Basel, Switzerland
Publisher MDPI AG
Language eng
Abstract Loss-of-function mutations of Na(V)1.7 lead to congenital insensitivity to pain, a rare condition resulting in individuals who are otherwise normal except for the inability to sense pain, making pharmacological inhibition of Na(V)1.7 a promising therapeutic strategy for the treatment of pain. We characterized a novel mouse model of Na(V)1.7-mediated pain based on intraplantar injection of the scorpion toxin OD1, which is suitable for rapid in vivo profiling of Na(V)1.7 inhibitors. Intraplantar injection of OD1 caused spontaneous pain behaviors, which were reversed by co-injection with Na(V)1.7 inhibitors and significantly reduced in Na(V)1.7(-/-) mice. To validate the use of the model for profiling Na(V)1.7 inhibitors, we determined the Na-V selectivity and tested the efficacy of the reported Na(V)1.7 inhibitors GpTx-1, PF-04856264 and CNV1014802 (raxatrigine). GpTx-1 selectively inhibited Na(V)1.7 and was effective when co-administered with OD1, but lacked efficacy when delivered systemically. PF-04856264 state-dependently and selectively inhibited Na(V)1.7 and significantly reduced OD1-induced spontaneous pain when delivered locally and systemically. CNV1014802 state-dependently, but non-selectively, inhibited Na-V channels and was only effective in the OD1 model when delivered systemically. Our novel model of Na(V)1.7-mediated pain based on intraplantar injection of OD1 is thus suitable for the rapid in vivo characterization of the analgesic efficacy of Na(V)1.7 inhibitors.
Formatted abstract
Loss-of-function mutations of NaV1.7 lead to congenital insensitivity to pain, a rare condition resulting in individuals who are otherwise normal except for the inability to sense pain, making pharmacological inhibition of NaV1.7 a promising therapeutic strategy for the treatment of pain. We characterized a novel mouse model of NaV1.7-mediated pain based on intraplantar injection of the scorpion toxin OD1, which is suitable for rapid in vivo profiling of NaV1.7 inhibitors. Intraplantar injection of OD1 caused spontaneous pain behaviors, which were reversed by co-injection with NaV1.7 inhibitors and significantly reduced in NaV1.7−/− mice. To validate the use of the model for profiling NaV1.7 inhibitors, we determined the NaV selectivity and tested the efficacy of the reported NaV1.7 inhibitors GpTx-1, PF-04856264 and CNV1014802 (raxatrigine). GpTx-1 selectively inhibited NaV1.7 and was effective when co-administered with OD1, but lacked efficacy when delivered systemically. PF-04856264 state-dependently and selectively inhibited NaV1.7 and significantly reduced OD1-induced spontaneous pain when delivered locally and systemically. CNV1014802 state-dependently, but non-selectively, inhibited NaV channels and was only effective in the OD1 model when delivered systemically. Our novel model of NaV1.7-mediated pain based on intraplantar injection of OD1 is thus suitable for the rapid in vivo characterization of the analgesic efficacy of NaV1.7 inhibitors.
Keyword CNV1014802
GpTx-1
NaV1.7
OD1
Pain
PF-04856264
Raxatrigine
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID FT130101215
RE 704/2-1 (AOBJ) 568743
569927
LP130101131
Institutional Status UQ
Additional Notes Article number 78

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Pharmacy Publications
Institute for Molecular Bioscience - Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 11 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 18 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Tue, 26 Apr 2016, 10:53:17 EST by System User on behalf of Learning and Research Services (UQ Library)