Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice

Brain. 2022 Oct 21;145(10):3637-3653. doi: 10.1093/brain/awab482.

Abstract

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.

Keywords: C-low threshold mechanoreceptors; Nav1.7; affective touch; congenital insensitivity to pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Mechanoreceptors
  • Mice
  • NAV1.7 Voltage-Gated Sodium Channel* / genetics
  • Pain Insensitivity, Congenital* / genetics
  • Sodium

Substances

  • NAV1.7 Voltage-Gated Sodium Channel
  • Sodium
  • SCN9A protein, human
  • Scn9a protein, mouse

Supplementary concepts

  • Indifference to Pain, Congenital, Autosomal Recessive