H2S functions as a nociceptive messenger through transient receptor potential ankyrin 1 (TRPA1) activation

Abstract Hydrogen sulfide (H 2 S), an endogenous gasotransmitter, modulates various biological functions, including nociception. It is known that H 2 S causes neurogenic inflammation and elicits hyperalgesia. Here we show that H 2 S activates mouse transient receptor potential ankyrin 1 (TRPA1) channels and elicits acute pain, using TRPA1-gene deficient mice (TRPA1(−/−)) and heterologous expression system. In wild-type mouse sensory neurons, H 2 S increased the intracellular Ca 2+ concentration ([Ca 2+ ] i ), which was inhibited by ruthenium red (a nonselective TRP channel blocker) and HC-030031 (a TRPA1 blocker). H 2 S-responsive neurons highly corresponded to TRPA1 agonist-sensitive ones. [Ca 2+ ] i responses to H 2 S were observed in neurons from transient receptor potential vanilloid 1 (TRPV1(−/−)) mice but not from TRPA1(−/−) mice. Heterologously expressed mouse TRPA1, but not mouse TRPV1, was activated by H 2 S. H 2 S-induced [Ca 2+ ] i responses were inhibited by dithiothreitol, a reducing agent. Analyses of the TRPA1 mutant channel revealed that two cysteine residues located in the N-terminal internal domain were responsible for the activation by H 2 S. Intraplantar injection of H 2 S into the mouse hind paw caused acute pain which was significantly less in TRPA1(−/−) mice. The [Ca 2+ ] i responses to H 2 S in sensory neurons and in heterologously expressed channels, and pain-related behavior induced by H 2 S were enhanced under acidic conditions. These results suggest that H 2 S functions as a nociceptive messenger through the activation of TRPA1 channels. TRPA1 may be a therapeutic target for H 2 S-related algesic action, especially under inflammatory conditions.