PROJECT SUMMARY/ABSTRACT Hypersensitivity of the urogenital organs and pelvic region is associated with urologic chronic pelvic pain syndrome (UCPPS; inclusive of interstitial cystitis/painful bladder syndrome and chronic prostatitis). Evidence from animal models demonstrates that central nervous system processing of urogenital/pelvic sensory information may be modified individually by (i) neonatal events that occur during sensory development and that permanently alter neuroanatomical substrates, or (ii) adverse events, such as stress or trauma, experienced during development or adulthood. Both of these phenomena have a high degree of clinical relevance, and there is good reason to believe that consequential alterations in the phenotype and function of primary afferent neurons innervating the urogenital and pelvic region are critical for the development of hypersensitivity and, thus, would serve as targets for therapeutic intervention. The long-term goal of this project is to systematically study changes in primary afferent-to-spinal cord sensory processing of somatic and visceral urogenital structures in clinically relevant animal models of UCPPS. The objective of the current proposal is to systematically examine the effects of neonatal bladder inflammation (NBI) or maternal separation (NMS), alone and in combination with an adult insult of the same class (bladder re-inflammation, acute or chronic stress), on urogenital hypersensitivity and/or widespread pain. The guiding hypothesis that serves as the basis of this proposal is that experiencing early life inflammation or stress alters distinct subclasses of urogenital primary afferent and spinal dorsal horn neurons that, in turn, inhibit or augment urogenital sensitivity in the context of a secondary adult exposure to inflammation or stress. This hypothesis will be addressed in three specific aims using: 1) in vivo reflex behaviors coupled with optogenetic targeting of stratified neuronal populations to determine how NBI or NMS alter primary afferent- driven reflex behaviors, 2) patch-clamp and extracellular in vivo electrophysiology to characterize functional activity within urogenital afferent and spinal dorsal horn neuronal pathways following NBI or NMS, and 3) neurochemistry and optogenetics to identify neurochemical mediators and receptors/transducers in urogenital tissues, primary afferent neurons, and spinal dorsal horn involved in the development of pelvic hypersensitivity.

PROJECT NARRATIVE The prevalence of urologic chronic pelvic pain syndrome (UCPPS) in the United States is high, ranging from 14- 25% of men and women. The pathology of UCPPS is multifactorial and existing therapies are both limited and unsatisfactory, underscoring the need for preclinical models that are reflective of disease complexity to advance our mechanistic understanding and identify new treatment strategies. To achieve these goals, we propose to systematically phenotype a dual-insult, preclinical model with high relevance to the clinical condition in order to examine promising targetable units that individually or in combination alter the peripheral nervous system and lead to UCPPS.