BACKGROUND AND PURPOSEHydrogen sulfide (H2S), generated by enzymes such as cystathionine-g-lyase (CSE) from L-cysteine, facilitates pain signals by activating the Cav3.2 T-type Ca 2+ channels. Here, we assessed the involvement of the CSE/H2S/Cav3.2 pathway in cystitis-related bladder pain. EXPERIMENTAL APPROACHCystitis was induced by i.p. administration of cyclophosphamide in mice. Bladder pain-like nociceptive behaviour was observed and referred hyperalgesia was evaluated using von Frey filaments. Phosphorylation of ERK in the spinal dorsal horn was determined immunohistochemically following intravesical administration of NaHS, an H2S donor. KEY RESULTSCyclophosphamide caused cystitis-related symptoms including increased bladder weight, accompanied by nociceptive changes (bladder pain-like nociceptive behaviour and referred hyperalgesia). Pretreatment with DL-propargylglycine, an inhibitor of CSE, abolished the nociceptive changes and partly prevented the increased bladder weight. CSE protein in the bladder was markedly up-regulated during development of cystitis. Mibefradil or NNC 55-0396, blockers of T-type Ca 2+ channels, administered after the symptoms of cystitis appeared, reversed the nociceptive changes. Further, silencing of Cav3.2 protein by repeated intrathecal administration of mouse Cav3.2-targeting antisense oligodeoxynucleotides also significantly attenuated the nociceptive changes, but not the increased bladder weight. Finally, the number of cells staining positive for phospho-ERK was increased in the superficial layer of the L6 spinal cord after intravesical administration of NaHS, an effect inhibited by NNC 55-0396. CONCLUSION AND IMPLICATIONSEndogenous H2S, generated by up-regulated CSE, caused bladder pain and referred hyperalgesia through the activation of Cav3.2 channels, one of the T-type Ca 2+ channels, in mice with cyclophosphamide-induced cystitis. Abbreviations
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