結腸の疼痛及び炎症におけるガス状情報伝達物質硫化水素の役割

抄録

  Hydrogen sulfide (H₂S), the third known gaseous transmitter following nitric oxide and carbon monoxide, is generated by multiple enzymes including cystathionine-γ-lyase (CSE) in vivo. We previously demonstrated that H₂S activates Ca_v3.2 T-type Ca²⁺ channels expressed on sensory neurons, leading to hyperalgesia and facilitation of inflammation. Here, we describe the role of H₂S in processing of colonic pain and inflammation. Intracolonic (i.col.) administration of NaHS, an H₂S donor, to mice evoked colonic pain-like nociceptive behavior and referred hyperalgesia accompanied by phosphorylation of ERK in the superficial layers of spinal dorsal horn, a marker for excitation of nociceptive neurons. The pronociceptive effect of NaHS was abolished by inhibitors or knockdown of Ca_v3.2 and by an inhibitor of TRPA1, another target molecule of H₂S. In rats with colitis induced by 2,4,6-trinitrobenzenesulfonic acid (TNBS), on the other hand, repeated i.col. administration of NaHS prevented colonic ulcer and inflammatory symptoms, which were inhibited by ablation of capsaicin-sensitive sensory neurons or T-type Ca²⁺ channel inhibitor. NaHS, given i.col., caused phosphorylation of ERK in the spinal dorsal horn of rats with TNBS-induced colitis, but not of naïve rats. In TNBS-treated rats, Ca_v3.2 was upregulated in the dorsal root ganglia, while CSE was downregulated in the colon. Taken together, these findings suggest that inhibitors of the CSE/H₂S/Ca_v3.2 or TRPA1 pathways might be useful for the treatment of colonic pain diseases such as irritable bowel syndrome, while H₂S donors or Ca_v3.2 activators might be useful for the treatment of inflammatory bowel disease including Crohn's disease.