Girard Beatrice M, Malley Susan E, Mathews Morgan M, May Victor, Vizzard Margaret A
Department of Neurological Sciences, College of Medicine, University of Vermont, D405A Given Research Building, Burlington, VT, 05405, USA.
J Mol Neurosci. 2016 Jun;59(2):290-9. doi: 10.1007/s12031-016-0764-1. Epub 2016 May 4.
Chronic NGF overexpression (OE) in the urothelium, achieved through the use of a highly urothelium-specific uroplakin II promoter, stimulates neuronal sprouting in the urinary bladder, produces increased voiding frequency and non-voiding contractions, and referred somatic sensitivity. Additional NGF-mediated pleiotropic changes might contribute to increased voiding frequency and pelvic hypersensitivity in NGF-OE mice such as neuropeptide/receptor systems including PACAP(Adcyap1) and PAC1 receptor (Adcyap1r1). Given the presence of PAC1-immunoreactive fibers and the expression of PAC1 receptor expression in bladder tissues, and PACAP-facilitated detrusor contraction, whether PACAP/receptor signaling contributes to increased voiding frequency and somatic sensitivity was evaluated in NGF-OE mice. Intravesical administration of the PAC1 receptor antagonist, PACAP(6-38) (300 nM), significantly (p ≤ 0.01) increased intercontraction interval (2.0-fold) and void volume (2.5-fold) in NGF-OE mice. Intravesical instillation of PACAP(6-38) also decreased baseline bladder pressure in NGF-OE mice. PACAP(6-38) had no effects on bladder function in WT mice. Intravesical administration of PACAP(6-38) (300 nM) significantly (p ≤ 0.01) reduced pelvic sensitivity in NGF-OE mice but was without effect in WT mice. PACAP/receptor signaling contributes to the increased voiding frequency and pelvic sensitivity observed in NGF-OE mice.
通过使用高度尿路上皮特异性的uroplakin II启动子，使尿路上皮慢性过表达神经生长因子（NGF），可刺激膀胱中的神经元发芽，增加排尿频率和非排尿收缩，并导致躯体感觉过敏。NGF介导的其他多效性变化可能导致NGF过表达（OE）小鼠的排尿频率增加和盆腔超敏反应，例如包括垂体腺苷酸环化酶激活肽（PACAP，Adcyap1）和PAC1受体（Adcyap1r1）在内的神经肽/受体系统。鉴于膀胱组织中存在PAC1免疫反应性纤维和PAC1受体表达，以及PACAP促进逼尿肌收缩，因此在NGF-OE小鼠中评估了PACAP/受体信号传导是否导致排尿频率增加和躯体感觉过敏。向膀胱内注射PAC1受体拮抗剂PACAP(6-38)（300 nM）可显著（p≤0.01）增加NGF-OE小鼠的收缩间隔（2.0倍）和排尿量（2.5倍）。向膀胱内滴注PACAP(6-38)也可降低NGF-OE小鼠的基线膀胱压力。PACAP(6-38)对野生型（WT）小鼠的膀胱功能无影响。向膀胱内注射PACAP(6-38)（300 nM）可显著（p≤0.01）降低NGF-OE小鼠的盆腔敏感性，但对WT小鼠无效。PACAP/受体信号传导导致了在NGF-OE小鼠中观察到的排尿频率增加和盆腔敏感性增加。
