PACAP/PAC1R signaling and CRH intersections in micturition circuits: effects of stress and injury/inflammation

Project Summary/Abstract 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) overall hypothesis that increases in urinary frequency and pelvic pain from stress- and inflammation/injury-induced changes in central micturition and peripheral sensory circuits reflect pituitary adenylate cyclase activating polypeptide (PACAP)/PAC1 receptor mediated signaling and corticotropin releasing hormone (CRH) interactions to engender a pro-excitatory state and cyclophosphamide (CYP) injury/inflammation models to test the . Building from our previous work, we will assess how maladaptive intersections between the CRH and PACAP/PAC1R central micturition neurocircuits and peripheral lower urinary tract (LUT) pathways may be contributory to stress-induced urinary bladder dysfunction and pelvic pain. Aim 1: To test whether RVS induces changes in CRH and PACAP/PAC1R expression and neuroplasticity in the pontine micturition complex (PMC; Barrington’s nucleus). Hypothesis: Our previous studies have demonstrated PACAP/PAC1R phenotypic plasticity after stress challenges. In concert, we anticipate that RVS will similarly result in central micturition pathway PACAP/PAC1R and CRH plasticity to alter voiding and pain responses. Aim 2: To test whether modulating PMC PACAPergic system and downstream CRH signaling alters voiding frequency and/or pelvic pain. Hypothesis: Regulation of PACAPergic signaling and CRH interactions in the PMC will modulate micturition and somatic sensitivity responses in normal and stressed states. Aim 3: To test whether modulating PACAP/PAC1R signaling and CRH pathways in the sensory components of the micturition reflex alters CYP- and RVS-induced voiding frequency and pelvic pain sensitivity. Hypothesis: We have shown previously that CYP-induced cystitis increases PACAP expression and signaling in sensory neurons. Accordingly, we hypothesize that blocking enhanced PACAP/PAC1 signaling from stress and injury/inflammation-induced plasticity in mice decreases voiding frequency and pelvic pain in part by modulating urothelium function. These studies are significant in advancing: (1) mechanistic insights to the underlying structural and functional changes contributory to stress- and injury/inflammation-induced changes in voiding behavior and pelvic pain; (2) the effects of psychological stress on central circuits underlying bladder function and pelvic sensation and (3) identification PACAP/PAC1R-mediated signaling and interactions with CRH/urocortin pathways as novel targets for stress- and injury/inflammation-induced urinary bladder dysfunction and pelvic pain.