Pain mechanisms in the female reproductive tract

Project Summary/Abstract Pelvic pain is a significant health burden affecting a large proportion of women worldwide. Up to 11% of women are diagnosed with endometriosis, and 80% may develop fibroids, with 25-50% experiencing pain symptoms. Additionally, many women experience chronic pelvic pain of unknown origin. These conditions have a staggering economic impact, with annual healthcare costs exceeding $10 billion in the United States alone, and profoundly affect quality of life, causing chronic pain, reduced productivity, and impaired social functioning. Despite the high prevalence and substantial impact on quality of life, the sensory mechanisms underlying female reproductive pain remain poorly understood, hindering the development of effective therapies. In other visceral organs such as the intestine and lung, serotonin and ATP have been shown to transmit nocifensive signals that initiate pain sensation. In the gut, serotonin-producing enterochromaffin cells act as polymodal stress sensors, releasing serotonin and ATP to activate gut-innervating sensory neurons and evoke nausea and pain. Similarly, in the lung, pulmonary neuroendocrine cells release ATP to trigger protective respiratory reflexes. This proposal aims to elucidate the role of serotonergic and purinergic signaling pathways in mediating nociception within the female reproductive tract. Our preliminary data show that serotonin-producing cells and serotonin-sensitive nerve fibers are present in the female reproductive tract. We hypothesize that these serotonergic and purinergic pathways serve as key components of nocifensive sensory circuits, analogous to their roles in other visceral organs. To test this hypothesis, we will employ state-of-the-art techniques, including genetically encoded neurotransmitter sensors and optogenetic tools, to characterize the molecular and functional properties of these signaling pathways. In Aim 1, we will identify the source of serotonin and characterize the stimuli that trigger its release. Aim 2 will investigate the functional connectivity between serotonin-producing cells and sensory neurons, and assess the behavioral consequences of activating this pathway, including pain responses. Aim 3 will focus on identifying the cellular origin of ATP and its role in nocifensive signaling. By delineating these novel sensory circuits, we aim to bridge the critical gap in understanding pelvic pain and create new intellectual space for developing targeted therapies in Women's Health. This research has the potential to transform our understanding of female reproductive pain and guide the development of novel, mechanism-based interventions for endometriosis, fibroids, and other debilitating conditions affecting millions of women worldwide.