TRPV1 Mediates Progressive Stress-Induced Bladder Dysfunction

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SUMMARY Stress-induced bladder dysfunction (SIBD) in children can manifest as overactive bladder (OAB) or underactive bladder/incomplete bladder emptying (UAB). Bladder dysfunction affects children medically, socially, emotionally and behaviorally; yet treatment options are limited and often ineffective. Recently, we have implicated transient receptor potential vanilloid family type1 (TRPV1) channels in the pathophysiology of adult OAB, but their roles in SIBD are unknown. Juvenile mice subjected to social stress developed OAB or UAB, depending on the intensity and duration of the stress. When social stress caused overactivity, TRPV1-mediated bladder afferent activity increased that was wholly absent in unstressed mice. When social stress caused underactivity, afferent activity was unchanged, but bladders were significantly remodeled and decompensated. Interestingly, TRPV1-KO mice developed no SIBD or any kind, regardless of the intensity or duration of social stress. Thus, Thus, we hypothesize that SIBD is progressive, such that (1) stress increases TRPV1-dependent afferent nerve activity, leading to bladder overactivity; (2) these aberrant signals to the central nervous system (CNS) coupled with bladder overactivity itself result in bladder remodeling; and (3) this remodeling decreases bladder compliance, afferent outflow and muscle contractility, leading to underactivity and ultimately urinary retention. This proposal will mechanistically investigate the onset and progression of SIBD through our unique murine model of stress-induced bladder dysfunction, which closely models pediatric bladder pathology. In this proposal, we will investigate how the duration/intensity of social stress causes bladder dysfunction and determine the role TRPV1 channels play in the progression of SIBD. We will deploy a wide array of techniques (histology, fluorescent in situ hybridization, ex vivo afferent nerve recordings, imaging, cystometry, conscious voiding behavior) and an array of transgenic and knockout mouse models to explore the pathophysiology of SIBD and determine how TRPV1 channels affect bladder function. The idea that both bladder overactivity and underactivity develop from aberrant TRPV1 channel sensitization simplifies our understanding of how stress causes bladder dysfunction and may lead to effective treatments for this debilitating condition.