Involvement of the cystathionine-γ-lyase/Cav3.2 pathway in substance P-induced bladder pain in the mouse, a model for nonulcerative bladder pain syndrome. (1st May 2018)

• Record Type: Journal Article
• Authors: Tsubota, Maho; Okawa, Yasumasa; Irie, Yuhei; Maeda, Mariko; Ozaki, Tomoka; Sekiguchi, Fumiko; Ishikura, Hiroyasu; Kawabata, Atsufumi
• Is Part Of: Neuropharmacology. Volume 133(2018)
• Page Start: 254
• Page End: 263
• Publication Date: 2018-05-01
• Subjects: Hydrogen sulfide -- T-type calcium channel -- Bladder pain syndrome -- Interstitial cystitis -- Substance P; BPS bladder pain syndrome -- CPA cyclophosphamide -- CSE cystathionine-γ-lyase -- IC interstitial cystitis -- ODN oligodeoxynucleotide -- PPG dl-propargylglycine; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2018.01.037
• Languages: English
• ISSNs: 0028-3908

Abstract

Abstract: Hydrogen sulfide (H2 S) formed by cystathionine-γ-lyase (CSE) enhances the activity of Cav 3.2 T-type Ca 2+ channels, contributing to the bladder pain accompanying hemorrhagic cystitis caused by systemic administration of cyclophosphamide (CPA) in mice. Given clinical and fundamental evidence for the involvement of the substance P/NK1 receptor systems in bladder pain syndrome (BPS)/interstitial cystitis (IC), we created an intravesical substance P-induced bladder pain model in mice and analyzed the possible involvement of the CSE/Cav 3.2 pathway. Bladder pain/cystitis was induced by i.p. CPA or intravesical substance P in female mice. Bladder pain was evaluated by counting nociceptive behavior and by detecting referred hyperalgesia in the lower abdomen and hindpaw. The isolated bladder tissue was weighed to estimate bladder swelling and subjected to histological observation and Western blotting. Intravesical substance P caused profound referred hyperalgesia accompanied by little bladder swelling or edema 6-24 h after the administration, in contrast to i.p. CPA-induced nociceptive behavior/referred hyperalgesia with remarkable bladder swelling/edema and urothelial damage. The bladder pain and/or cystitis symptoms caused by substance P or CPA were prevented by the NK1 receptor antagonist. CSE in the bladder was upregulated by substance P or CPA, and the NK1 antagonist prevented the CPA-induced CSE upregulation. A CSE inhibitor, a T-type Ca 2+ channel blocker and gene silencing of Cav 3.2 abolished the intravesical substance P-induced referred hyperalgesia. The intravesical substance P-induced pain in mice is useful as a model for nonulcerative BPS, and involves the activation of the NK1 receptor/CSE/H2 S/Cav 3.2 cascade. Highlights: Intravesical substance P caused bladder pain with little urothelial damage. Substance P upregulated an H2 S-forming enzyme in the bladder. Inhibition of the H2 S-forming enzyme blocked the substance P-induced bladder pain. Cav 3.2 knockdown abolished the substance P-induced bladder pain. Cav 3.2 targeted by H2 S thus mediates the substance P-induced bladder pain.