TRPA1 Has a Key Role in the Somatic Pro-Nociceptive Actions of Hydrogen Sulfide

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Abstract

Hydrogen sulfide (H2S), which is produced endogenously from L-cysteine, is an irritant with pro-nociceptive actions. We have used measurements of intracellular calcium concentration, electrophysiology and behavioral measurements to show that the somatic pronociceptive actions of H2S require TRPA1. A H2S donor, NaHS, activated TRPA1 expressed in CHO cells and stimulated DRG neurons isolated from Trpa1(+/+) but not Trpa1(-/-) mice. TRPA1 activation by NaHS was pH dependent with increased activity at acidic pH. The midpoint of the relationship between NaHS EC50 values and external pH was pH 7.21, close to the expected dissociation constant for H2S (pK(a) 7.04). NaHS evoked single channel currents in inside-out and cell-attached membrane patches consistent with an intracellular site of action. In behavioral experiments, intraplantar administration of NaHS and L-cysteine evoked mechanical and cold hypersensitivities in Trpa1(+/+) but not in Trpa1(-/-) mice. The sensitizing effects of L-cysteine in wild-type mice were inhibited by a cystathionine beta-synthase inhibitor, D, L-propargylglycine (PAG), which inhibits H2S formation. Mechanical hypersensitivity evoked by intraplantar injections of LPS was prevented by PAG and the TRPA1 antagonist AP-18 and was absent in Trpa1(-/-) mice, indicating that H2S mediated stimulation of TRPA1 is necessary for the local pronociceptive effects of LPS. The pro-nociceptive effects of intraplantar NaHS were retained in Trpv1(-/-) mice ruling out TRPV1 as a molecular target. In behavioral studies, NaHS mediated sensitization was also inhibited by a T-type calcium channel inhibitor, mibefradil. In contrast to the effects of NaHS on somatic sensitivity, intracolonic NaHS administration evoked similar nociceptive effects in Trpa1(+/+) and Trpa1(-/-) mice, suggesting that the visceral pro-nociceptive effects of H2S are independent of TRPA1. In electrophysiological studies, the depolarizing actions of H2S on isolated DRG neurons were inhibited by AP-18, but not by mibefradil indicating that the primary excitatory effect of H2S on DRG neurons is TRPA1 mediated depolarization.

Original languageEnglish
Article numbere46917
Pages (from-to)-
Number of pages9
JournalPL o S One
Volume7
Issue number10
DOIs
Publication statusPublished - 11 Oct 2012

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