PACAP/PAC1 receptor signaling in micturition neurocircuits: effects of stress and injury/inflammation

(请保存在Word中，不要保存为PDF) 膀胱疼痛综合征(BPS)/间质性膀胱炎(IC)是一种以耻骨上骨盆疼痛为特征的慢性盆腔疼痛疾病，至少有一种尿路症状。压力会加重BPS/IC的症状。尽管进行了大量的研究，但我们缺乏对排尿反射的结构和功能变化如何与BPS/IC有关的了解，以及压力如何加剧症状，从而阻碍有效的治疗。在我们以前合作的基础上，整合了我们不同的科学学科，结合了我们独特的实验室优势，我们将使用重复变量应激(RVS)和环磷酰胺(CYP)损伤/炎症模型来检验总体假设，即应激和损伤分别导致中枢排尿和外周感觉回路变化导致尿频和盆腔疼痛反应增加，反映PACAP/PAC1受体介导的信号和神经可塑性，从而产生亲兴奋状态。在我们以前工作的基础上，我们将评估PACAP/PAC1R通路之间的不适应交叉点如何可能导致应激诱导的膀胱功能障碍和骨盆疼痛。目的1：检测RVS在没有直接膀胱损伤的情况下，是否诱导与中枢神经回路PACAP/PAC1R神经化学可塑性相关的排尿反射的改变。假设：我们以前的研究已经证明了神经肽的表型可塑性，包括应激挑战后PACAP/PAC1R表达的变化。与这些反应相协调，我们预计RVS和CYP挑战将类似地导致中枢排尿途径PACAP/PAC1R可塑性改变排尿和疼痛反应。这些研究在以下方面具有重要意义：(1)从机制上深入了解导致应激和损伤/炎症诱导的排尿行为和盆腔疼痛的潜在结构和功能变化；(2)心理应激对潜在的膀胱功能和盆腔感觉的中枢回路的影响；(3)确认PACAP/PAC1受体介导的信号转导是应激和损伤/炎症诱导的膀胱功能障碍和盆腔疼痛的新靶点。

(PLEASE KEEP IN WORD, DO NOT PDF) Bladder Pain Syndrome (BPS)/ Interstitial Cystitis (IC) is a chronic pelvic pain disorder characterized by suprapubic, pelvic pain with at least one urinary symptom. Stress exacerbates symptoms of BPS/IC. Despite intense research, we lack understanding of how structural and functional changes in the micturition reflex are linked to BPS/IC and how stress exacerbates symptoms, thus impeding effective therapies. Expanding upon our previous collaborations, integrating our diverse scientific disciplines, and combining our unique laboratory strengths, we will use a repeated variate stress (RVS) and cyclophosphamide (CYP) injury/inflammation models to test the overall hypothesis that increases in urinary frequency and pelvic pain responses from stress- and injury-induced changes in central micturition and peripheral sensory circuits, respectively, reflect PACAP/PAC1 receptor-mediated signaling and neuroplasticity to engender a pro-excitatory state. Building from our previous work, we will assess how maladaptive intersections between the PACAP/PAC1R pathways may be contributory to stress-induced urinary bladder dysfunction and pelvic pain. Aim 1: To test whether RVS, in the absence of direct urinary bladder insults, induces changes in micturition reflexes that are associated with PACAP/PAC1R neurochemical plasticity in central neural circuits. Hypothesis: Our previous studies have demonstrated neuropeptide phenotypic plasticity, including changes in PACAP/PAC1R expression after stress challenges. Coordinate with these responses, we anticipate that RVS and CYP challenges will similarly result in central micturition pathway PACAP/PAC1R plasticity to alter voiding and pain responses. These studies are significant in the: (1) mechanistic insight gained of underlying structural and functional changes contributory to stress- and injury/inflammation-induced changes in voiding behavior and pelvic pain; (2) influence of psychological stress on central circuits underlying bladder function and pelvic sensation and (3) identification PACAP/PAC1 receptor-mediated signaling as a novel target for stress- and injury/inflammation-induced urinary bladder dysfunction and pelvic pain.