Subtype-Selective Small Molecule Inhibitors Reveal a Fundamental Role for Nav1.7 in Nociceptor Electrogenesis, Axonal Conduction and Presynaptic Release

PLoS One. 2016 Apr 6;11(4):e0152405. doi: 10.1371/journal.pone.0152405. eCollection 2016.

Abstract

Human genetic studies show that the voltage gated sodium channel 1.7 (Nav1.7) is a key molecular determinant of pain sensation. However, defining the Nav1.7 contribution to nociceptive signalling has been hampered by a lack of selective inhibitors. Here we report two potent and selective arylsulfonamide Nav1.7 inhibitors; PF-05198007 and PF-05089771, which we have used to directly interrogate Nav1.7's role in nociceptor physiology. We report that Nav1.7 is the predominant functional TTX-sensitive Nav in mouse and human nociceptors and contributes to the initiation and the upstroke phase of the nociceptor action potential. Moreover, we confirm a role for Nav1.7 in influencing synaptic transmission in the dorsal horn of the spinal cord as well as peripheral neuropeptide release in the skin. These findings demonstrate multiple contributions of Nav1.7 to nociceptor signalling and shed new light on the relative functional contribution of this channel to peripheral and central noxious signal transmission.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Axons / physiology*
  • Ganglia, Spinal / drug effects
  • Ganglia, Spinal / physiology
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • NAV1.7 Voltage-Gated Sodium Channel / drug effects*
  • NAV1.7 Voltage-Gated Sodium Channel / physiology
  • Patch-Clamp Techniques
  • Phenyl Ethers / pharmacology
  • Presynaptic Terminals / physiology*
  • Sulfonamides / pharmacology

Substances

  • NAV1.7 Voltage-Gated Sodium Channel
  • PF-05089771
  • Phenyl Ethers
  • Sulfonamides

Grant support

The funder provided support in the form of salaries for authors [AA, AB, MC, JT, MM, AW, EP, AG, PJC, RD, DP, ZL, BM, CW, NS, RS, PS, NC, DK, RB, ES], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section.