Pharmacological blockade of TRPA1 inhibits mechanical firing in nociceptors.
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.


CONCLUSIONS
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.
Kerstein
Patrick C
PC
Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA. pkerstein@mcw.edu
del Camino
Donato
D
Moran
Magdalene M
MM
Stucky
Cheryl L
CL
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D002211:Capsaicin / Q000494:pharmacology; D005260:Female; D005557:Formaldehyde / Q000494:pharmacology; D008297:Male; D049990:Membrane Transport Modulators / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000502:physiology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000502:physiology; D009619:Nociceptors / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors* / Q000172:deficiency
D049990:Membrane Transport Modulators; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D005557:Formaldehyde; D002211:Capsaicin