Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan.
Laboratory of Pharmacology and Pathophysiology, Faculty of Pharmacy, Kindai University, 3-4-1 Kowakae, Higashi-Osaka 577-8502, Japan; Division of Emergency and Critical Care Medicine, Fukuoka University, Hospital, Fukuoka 814-0180, Japan.
Neuropharmacology. 2018 May 1;133:254-263. doi: 10.1016/j.neuropharm.2018.01.037. Epub 2018 Jan 31.
Hydrogen sulfide (HS) formed by cystathionine-γ-lyase (CSE) enhances the activity of Ca3.2 T-type Ca 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/NK 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/Ca3.2 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 NK receptor antagonist. CSE in the bladder was upregulated by substance P or CPA, and the NK antagonist prevented the CPA-induced CSE upregulation. A CSE inhibitor, a T-type Ca channel blocker and gene silencing of Ca3.2 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 NK receptor/CSE/HS/Ca3.2 cascade.
硫化氢（HS）由胱硫醚γ裂解酶（CSE）形成，增强了 Ca3.2T 型钙通道的活性，导致环磷酰胺（CPA）全身给药引起的小鼠出血性膀胱炎时膀胱疼痛。鉴于 P 物质/NK 受体系统在膀胱疼痛综合征（BPS）/间质性膀胱炎（IC）中的参与有临床和基础证据，我们在小鼠中创建了一种膀胱内 P 物质诱导的膀胱疼痛模型，并分析了 CSE/Ca3.2 通路的可能参与。雌性小鼠通过腹腔内 CPA 或膀胱内 P 物质诱导膀胱疼痛/膀胱炎。通过计数伤害性行为和检测下腹部和后脚的牵涉性痛觉过敏来评估膀胱疼痛。将分离的膀胱组织称重以估计膀胱肿胀，并进行组织学观察和 Western blot 分析。与 i.p.CPA 引起的伤害性行为/牵涉性痛觉过敏伴显著膀胱肿胀/水肿和尿路上皮损伤相比，膀胱内 P 物质引起的牵涉性痛觉过敏在给药后 6-24 小时内引起强烈的牵涉性痛觉过敏，而膀胱肿胀或水肿很少。P 物质或 CPA 引起的膀胱疼痛和/或膀胱炎症状可被 NK 受体拮抗剂预防。P 物质或 CPA 上调膀胱中的 CSE，而 NK 拮抗剂可预防 CPA 诱导的 CSE 上调。CSE 抑制剂、T 型钙通道阻滞剂和 Ca3.2 的基因沉默消除了膀胱内 P 物质诱导的牵涉性痛觉过敏。在小鼠中，膀胱内 P 物质引起的疼痛可作为非溃疡性 BPS 的模型，涉及 NK 受体/CSE/HS/Ca3.2 级联的激活。
