title: Hydrogen sulfide-induced itch requires activation of Cav3.2 T-type calcium channel in mice.
abstract: The contributions of gasotransmitters to itch sensation are largely unknown. In this study, we aimed to investigate the roles of hydrogen sulfide (H2S), a ubiquitous gasotransmitter, in itch signaling. We found that intradermal injection of H2S donors NaHS or Na2S, but not GYY4137 (a slow-releasing H2S donor), dose-dependently induced scratching behavior in a μ-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 Cav3.2 T-type calcium channel by mibefradil, ascorbic acid, zinc chloride or Cav3.2 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 H2S (L-cysteine) but attenuated by inhibitors of H2S-producing enzymes cystathionine γ-lyase and cystathionine β-synthase. These results indicated that H2S, as a novel nonhistaminergic itch mediator, may activates Cav3.2 T-type calcium channel, probably located at A-fibers, to induce scratching and alloknesis in mice.
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215021, China.
authors.forename: Xue-Long
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215021, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Tian
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215021, China.|Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, 215123, China.
authors.forename: Ya
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215021, China.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Peng
authors.affiliation: Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Soochow University, Suzhou, 215123, China.
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215021, China.
authors.forename: Jun-Cheng
authors.initials: JC
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and the Second Affiliated Hospital of Soochow University, Soochow University, Suzhou 215021, China.|Institute of Neuroscience, Soochow University, Suzhou, Jiangsu, 215123, China.
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
mesh_terms: D000083:Acetanilides / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020747:Calcium Channels, T-Type / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D003541:Cystathionine beta-Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology; D008297:Male; D020748:Mibefradil / Q000494:pharmacology; D051379:Mice; D011537:Pruritus / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology*; D011687:Purines / Q000494:pharmacology; D034622:RNA Interference; D011957:Receptors, Opioid / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000378:metabolism; D013440:Sulfides / Q000633:toxicity*; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C552888:2-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)-N-(4-isopropylphenyl)acetamide; D000083:Acetanilides; C504883:Cacna1h protein, mouse; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D004224:Diterpenes; D011687:Purines; D011957:Receptors, Opioid; D013440:Sulfides; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D020748:Mibefradil; C024353:resiniferatoxin; D003541:Cystathionine beta-Synthase; D003542:Cystathionine gamma-Lyase; C025451:sodium bisulfide; C071423:capsazepine; D002211:Capsaicin; C033479:sodium sulfide