Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors

Mol Pain. 2009 Apr 21;5:19. doi: 10.1186/1744-8069-5-19.

Abstract

Background: TRPA1 has been implicated in both chemo- and mechanosensation. Recent work demonstrates that inhibiting TRPA1 function reduces mechanical hypersensitivity produced by inflammation. Furthermore, a broad range of chemical irritants require functional TRPA1 to exert their effects. In this study we use the ex-vivo skin-nerve preparation to directly determine the contribution of TRPA1 to mechanical- and chemical-evoked responses at the level of the primary afferent terminal.

Results: Acute application of HC-030031, a selective TRPA1 antagonist, inhibited all formalin responses in rat C fibers but had no effect on TRPV1 function, assessed by capsaicin responsiveness. Genetic ablation experiments corroborated the pharmacological findings as C fibers from wild type mice responded to both formalin and capsaicin, but fibers from their TRPA1-deficient littermates responded only to capsaicin. HC-030031 markedly reduced the mechanically-evoked action potential firing in rat and wild type mouse C fibers, particularly at high-intensity forces, but had no effect on the mechanical responsiveness of Adelta fiber nociceptors. Furthermore, HC-030031 had no effect on mechanically-evoked firing in C fibers from TRPA1-deficient mice, indicating that HC-030031 inhibits mechanically-evoked firing via a TRPA1-dependent mechanism.

Conclusion: Our data show that acute pharmacological blockade of TRPA1 at the cutaneous receptive field inhibits formalin-evoked activation and markedly reduces mechanically-evoked action potential firing in C fibers. Thus, functional TRPA1 at sensory afferent terminals in skin is required for their responsiveness to both noxious chemical and mechanical stimuli.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Action Potentials / drug effects*
  • Animals
  • Capsaicin / pharmacology
  • Female
  • Formaldehyde / pharmacology
  • Male
  • Membrane Transport Modulators / pharmacology*
  • Mice
  • Mice, Knockout
  • Nerve Fibers, Myelinated / drug effects
  • Nerve Fibers, Myelinated / physiology
  • Nerve Fibers, Unmyelinated / drug effects
  • Nerve Fibers, Unmyelinated / physiology
  • Nociceptors / drug effects*
  • Nociceptors / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • TRPA1 Cation Channel
  • Transient Receptor Potential Channels / antagonists & inhibitors*
  • Transient Receptor Potential Channels / deficiency

Substances

  • Membrane Transport Modulators
  • TRPA1 Cation Channel
  • Transient Receptor Potential Channels
  • Trpa1 protein, mouse
  • Formaldehyde
  • Capsaicin