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Involvement of the endogenous hydrogen sulfide/Ca v 3.2 T‐type Ca 2+ channel pathway in cystitis‐related bladder pain in mice
Author(s) -
Matsunami Maho,
Miki Takahiro,
Nishiura Kanae,
Hayashi Yuko,
Okawa Yasumasa,
Nishikawa Hiroyuki,
Sekiguchi Fumiko,
Kubo Lisa,
Ozaki Tomoka,
Tsujiuchi Toshifumi,
Kawabata Atsufumi
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02060.x
Subject(s) - nociception , spinal cord , medicine , chemistry , pharmacology , urinary bladder , hyperalgesia , endocrinology , anesthesia , receptor , psychiatry
BACKGROUND AND PURPOSE Hydrogen sulfide (H 2 S), generated by enzymes such as cystathionine‐γ‐lyase (CSE) from L‐cysteine, facilitates pain signals by activating the Ca v 3.2 T‐type Ca 2+ channels. Here, we assessed the involvement of the CSE/H 2 S/Ca v 3.2 pathway in cystitis‐related bladder pain. EXPERIMENTAL APPROACH Cystitis 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 H 2 S donor. KEY RESULTS Cyclophosphamide 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 Ca v 3.2 protein by repeated intrathecal administration of mouse Ca v 3.2‐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 IMPLICATIONS Endogenous H 2 S, generated by up‐regulated CSE, caused bladder pain and referred hyperalgesia through the activation of Ca v 3.2 channels, one of the T‐type Ca 2+ channels, in mice with cyclophosphamide‐induced cystitis.