Wang Xue-Long, Tian Bin, Huang Ya, Peng Xiao-Yan, Chen Li-Hua, Li Jun-Cheng, Liu Tong
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.
Sci Rep. 2015 Nov 25;5:16768. doi: 10.1038/srep16768.
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.
气体递质对瘙痒感觉的作用在很大程度上尚不清楚。在本研究中，我们旨在探究硫化氢（H2S）这种普遍存在的气体递质在瘙痒信号传导中的作用。我们发现，皮内注射H2S供体硫氢化钠（NaHS）或硫化钠（Na2S），而非GYY4137（一种缓释H2S供体），能以剂量依赖性方式在小鼠中诱导搔抓行为，且该行为依赖于μ-阿片受体且不依赖组胺。有趣的是，NaHS通过独特机制诱导瘙痒，该机制涉及对辣椒素不敏感的A纤维，而非传统上认为介导瘙痒的表达瞬时受体电位香草酸亚型1（TRPV1）的C纤维，这一结论通过全身应用树脂毒素处理使表达TRPV1的C纤维耗竭得以揭示。此外，局部应用辣椒素受体拮抗剂（TRPV1阻断剂）或HC-030031（TRPA1阻断剂）对NaHS诱发的搔抓行为无影响。令人惊讶的是，米贝地尔、抗坏血酸、氯化锌或Cav3.2小干扰RNA对Cav3.2 T型钙通道进行药理学阻断和沉默后，能显著降低NaHS诱发的搔抓行为。NaHS可诱导强烈的异痒症（触摸诱发的瘙痒），该症状可被T型钙通道阻断剂米贝地尔抑制。化合物48/80诱发的瘙痒可被H2S的内源性前体（L-半胱氨酸）增强，但被H2S生成酶胱硫醚γ-裂解酶和胱硫醚β-合酶的抑制剂减弱。这些结果表明，H2S作为一种新型的非组胺能瘙痒介质，可能激活可能位于A纤维上的Cav3.2 T型钙通道，从而在小鼠中诱导搔抓行为和异痒症。
