Project Summary/Abstract Acute and chronic pains originating from the urinary bladder are common clinical entities affecting more than 50% of females at some time in their lives. In an attempt to understand urinary bladder hypersensitivity in a translational manner, this ongoing research project has used rodents to define basic neurophysiological elements of bladder sensation at spinal and supraspinal levels. Using urinary bladder distension (UBD)-evoked reflexes and spinal/supraspinal neuronal responses as experimental endpoints, clinically-relevant models of bladder hypersensitivity have been developed. The present application explores the role of corticotropin releasing factor receptors – type 2 (CRF2R) in this bladder hypersensitivity. Three Specific Aims are proposed: Specific Aim #1: To quantitatively characterize, using molecular and neurochemical measures, CRF2R expression and agonist peptide content in bladder primary afferent neurons (bPANs) & spinal cord of rats which had NBI & a second adult insult. Specific Aim #2: To quantitatively characterize effects of CRF2R agonists and antagonists on individual bPANs in rats which experienced NBI and a second adult insult. Specific Aim #3: To quantitatively characterize effects of CRF2R agonists and antagonists on spinal neuronal responses to UBD in rats which experienced NBI and a second adult insult. These studies will expand upon preliminary studies and will determine quantitatively the effects of the novel therapeutic agents, CRF2R-antagonists on primary afferent and spinal dorsal horn neuronal responses to UBD. Effects of pharmacological manipulations related to pain facilitation will be assessed in animals which experienced neonatal bladder inflammation and controls. The proposed studies in rodent model systems will give insight related to bladder pain and will explore novel therapeutics. An improved understanding of sensory processing related to IC and of urinary bladder sensory pathways and their modulation by secondary insults will result in an increased translation of basic science to therapeutics for bladder pain.

PROJECT NARRATIVE The proposed studies examining effects of neonatal bladder inflammation in rodent model systems will give insight related to a novel, non-opioid therapeutic mechanism using CRF2R-linked pharmacology. Neural pathways and mechanisms related to secondary insults such as stress and inflammation will be defined and novel expression of CRF2R mechanisms will be explored. An improved understanding of sensory processing related to IC and of urinary bladder sensory pathways and their modulation by acute stress and pharmacological manipulations will result in an increased translation of basic science to therapeutics for bladder pain.