Hydrogen sulfide (H_2S), a gasotransmitter, is endogenously formed from L-cysteine by certain enzymes including cystathionine-gamma-lyase (CSE) in the mammalian body. H_2S sensitizes Ca_v3.2T-type calcium channels, leading to excitation of sensory neurons followed by somatic hyperalgesia in rats and mice. The enhanced activity of the H_2S/Ca_v3.2 system is involved in the neuropathic pain/hyper-algesia induced by repeated administration of paclitaxel, an anti-cancer drug, or by spinal nerve injury. It is also noteworthy that the H_2S-induced mechanical hyperalgesia requires activation of both Ca_v3.2 and transient receptor potential A1 (TRPA1) channels in mice. H_2S and Ca_v3.2 T-type calcium channels are also involved in processing of visceral nociception including colonic, pancreatic and bladder pain. Endogenous H_2S formed by upregulated CSE contributes to the pancreatitis-related pain. Further, the excitation of sensory nerves by H_2S through T-type calcium channels exerts mucosal cytoprotection against colitis in rats. Together, endogenous H_2S formed by CSE appears to stimulate sensory nerves by targeting Ca_v3.2 T-type calcium channels and, in some cases, TRPA1 channels, leading to facilitation of somatic and visceral pain signals and also contributing to colonic mucosal cytoprotection. Thus, the CSE/H_2S/Ca_v3.2 system may serve as therapeutic targets for treatment of neuropathic or visceral pain and of colitis.
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