2. Academic Validation
  3. Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain

Analgesic Effects of GpTx-1, PF-04856264 and CNV1014802 in a Mouse Model of NaV1.7-Mediated Pain

  • Toxins (Basel). 2016 Mar 17;8(3):78. doi: 10.3390/toxins8030078.
Jennifer R Deuis 1 2,  Joshua S Wingerd 3,  Zoltan Winter 4,  Thomas Durek 5,  Zoltan Dekan 6,  Silmara R Sousa 7,  Katharina Zimmermann 8,  Tali Hoffmann 9,  Christian Weidner 10,  Mohammed A Nassar 11,  Paul F Alewood 12,  Richard J Lewis 13,  Irina Vetter 14 15
Affiliations

Affiliations

  • 1 Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. [email protected].
  • 2 School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia. [email protected].
  • 3 Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. [email protected].
  • 4 Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. [email protected].
  • 5 Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. [email protected].
  • 6 Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. [email protected].
  • 7 Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. [email protected].
  • 8 Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. [email protected].
  • 9 Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. [email protected].
  • 10 Department of Physiology and Pathophysiology and Department of Anaesthesiology, Friedrich-Alexander University Erlangen-Nuremberg, 91054 Erlangen, Germany. [email protected].
  • 11 Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN, UK. [email protected].
  • 12 Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. [email protected].
  • 13 Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. [email protected].
  • 14 Centre for Pain Research, Institute for Molecular Biosciences, The University of Queensland, St Lucia, QLD 4072, Australia. [email protected].
  • 15 School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia. [email protected].
PMID: 26999206 DOI: 10.3390/toxins8030078
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.

Keywords

CNV1014802; GpTx-1; NaV1.7; OD1; PF-04856264; pain; raxatrigine.

Figures
Products