Recurrent pain of the bladder, pelvis or urogenital floor is a defining feature of chronic pelvic pain syndromes including Interstitial Cystitis and Chronic Prostatitis. The causative pathology of these disorders is not known despite efforts to identify disease markers. The cell bodies of pain- sensing neurons, nociceptors, that innervate the lower urinary tract reside in the dorsal root ganglia amidst many other sensory neurons and can develop inappropriate activity following inflammation and infection. How these processes lead to altered sensitivity of nociceptors and set the stage for chronic pain is not completely understood. Throughout the nervous system serotonin (5-HT) exerts a wide range of effects on neurogenesis, differentiation, and maintenance of neurons and can act as an inflammatory neuromodulator. Signaling through serotonin receptors (5-HTRs) has been shown to modulate nociception and contributes to sensitization of the sensory neurons. The effects of signaling through 5-HTRs in the lower urinary tract have not been investigated in detail because even the cell-type specific distribution of these receptors has not been evaluated in this system. This research proposal aims to generate fundamental knowledge that will increase understanding of nociceptive processes in the bladder and urethra by identifying the distribution of 5-HTRs in pelvic innervation during development and maturation of the lower urinary tract. Transcriptional profiles of serotonergic lumbar and sacral sensory neurons will be derived to obtain a molecular fingerprint of the pelvic sensory neurons that express 5-HTRs. The results will establish a framework so that role of 5- HT signaling in the urogenital tract may be related to other nociceptors. To further elaborate links between 5-HT signaling and nociception, we will generate transgenic reporter mice that express multi-cistronic fluorescent reporter proteins in nociceptive sensory neurons. Multi- spectral transgene expression will enable simultaneous localization of cell nuclei, splasma membrane, and fluctuations in intracellular calcium within nociceptors. These reporters will enable direct imaging of cellular responses to pharmacological interventions and environmental assaults. The information gained will advance future studies of chronic visceral pain in the lower urinary tract and thus meet the criteria for inclusion in the Nociceptive GenitoUrinary Development Molecular Anatomy Project (nGUDMAP).
Chronic pain in the lower urinary tract is believed to originate from abnormal signals generated by nerves that monitor uncomfortable sensations in the bladder and urethra. The proposed work aims to help us better understand how chronic pain in these organs is transmitted by pinpointing the locations of signaling molecules expressed on nerves of these organs and by generating transgenic mice that will enable real time imaging of calcium signaling in the bladder. The results will identify drug targets for treating chronic bladdr pain and will allow direct visualization of cell signaling that occurs when candidate treatments are applied in animal models.