Plasticity in the sensory innervation of the urinary bladder underlies the pain accompanying inflammatory states, such as interstitial cystitis. Our recent studies on bladder sensory neurons and urothelium have revealed novel and powerful actions of estrogens on signaling processes in both types of ceils. These studies have also indicated the importance of defining how estrogens interact with other neuroactive molecules integral to inflammatory changes, such as nerve growth factor and ATP. Together, this work raises the possibility of identifying new pharmacological strategies for targeting and controlling plasticity in this system and hence reducing the associated pain. In this project we propose a comprehensive group of studies on bladder sensory neurons and urothelial cells to further explore the role of estrogens in modulating the activity of bladder sensory neurons and urothelium. Our goal is to identify the cellular mechanisms by which estrogens influence of the plasticity of bladder sensory pathways after acute and chronic inflammation. The major aims are: (1) To understand the mechanism by which estrogens affect the detection of noxious stimuli by the bladder, under normal and inflamed conditions;(2) To determine how estrogens affect the modulation of nociceptive signaling by other factors. To achieve these aims the project will combine an array of experimental approaches, including cell signaling studies, cultures of adult bladder sensory neurons, immunofluorescence and image analysis, patch clamp electrophysiology and a novel neuron-urothelium co-culture system. These studies will lead to advances in our understanding of estrogen actions on bladder afferent innervation, especially bladder nociception, and will provide important insights into bladder dysfunction, especially conditions involving inflammation. This may assist with the development of new strategies to counteract painful sequelae of bladder inflammation or blocking spread of pain to other pelvic viscera.
