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In this study, we aimed to investigate the roles of hydrogen sulfide (H<jats:sub>2<\/jats:sub>S), a ubiquitous gasotransmitter, in itch signaling. We found that intradermal injection of H<jats:sub>2<\/jats:sub>S donors NaHS or Na<jats:sub>2<\/jats:sub>S, but not GYY4137 (a slow-releasing H<jats:sub>2<\/jats:sub>S donor), dose-dependently induced scratching behavior in a \u03bc-opioid receptor-dependent and histamine-independent manner in mice. Interestingly, NaHS induced itch via unique mechanisms that involved capsaicin-insensitive A-fibers, but not TRPV1-expressing C-fibers that are traditionally considered for mediating itch, revealed by depletion of TRPV1-expressing C-fibers by systemic resiniferatoxin treatment. Moreover, local application of capsaizapine (TRPV1 blocker) or HC-030031 (TRPA1 blocker) had no effects on NaHS-evoked scratching. Strikingly, pharmacological blockade and silencing of Ca<jats:sub>v<\/jats:sub>3.2 T-type calcium channel by mibefradil, ascorbic acid, zinc chloride or Ca<jats:sub>v<\/jats:sub>3.2 siRNA dramatically decreased NaHS-evoked scratching. NaHS induced robust alloknesis (touch-evoked itch), which was inhibited by T-type calcium channels blocker mibefradil. Compound 48\/80-induced itch was enhanced by an endogenous precursor of H<jats:sub>2<\/jats:sub>S (L-cysteine) but attenuated by inhibitors of H<jats:sub>2<\/jats:sub>S-producing enzymes cystathionine \u03b3-lyase and cystathionine \u03b2-synthase. These results indicated that H<jats:sub>2<\/jats:sub>S, as a novel nonhistaminergic itch mediator, may activates Ca<jats:sub>v<\/jats:sub>3.2 T-type calcium channel, probably located at A-fibers, to induce scratching and alloknesis in mice.<\/jats:p>","DOI":"10.1038\/srep16768","type":"journal-article","created":{"date-parts":[[2015,11,25]],"date-time":"2015-11-25T09:26:42Z","timestamp":1448443602000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Hydrogen sulfide-induced itch requires activation of Cav3.2 T-type calcium channel in mice"],"prefix":"10.1038","volume":"5","author":[{"given":"Xue-Long","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Yan","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Hua","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Cheng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,11,25]]},"reference":[{"key":"BFsrep16768_CR1","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/nrn1950","volume":"7","author":"A Ikoma","year":"2006","unstructured":"Ikoma, A., Steinhoff, M., Stander, S., Yosipovitch, G. & Schmelz, M. 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