Cross-sensitization in the pelvis and neurogenic bladder

慢性盆腔疼痛是许多泌尿系统和胃肠道疾病的常见症状，包括间质性膀胱炎和肠易激综合征。盆腔器官间的交叉致敏导致病因不明的慢性盆腔疼痛。我们的长期目标是阐明骨盆交叉致敏的神经、神经体液和神经免疫机制，并揭示其与神经源性炎症和慢性骨盆疼痛发生的相关性。最近的研究表明感觉传入通路在盆腔器官交叉致敏中的作用，然而，我们对其潜在机制的理解仍然是初级的。我们假设，由于脊髓和背根神经节（DRG）传入感觉通路的敏化，结肠炎症改变了膀胱的功能。我们认为，结肠炎症引起的DRG和脊髓感觉神经元兴奋性增强，改变了促炎神经肽的表达及其在膀胱中的释放，导致后者发生神经源性炎症。将进行神经解剖学、免疫组织化学、电生理学和神经药理学研究，以表征感觉神经通路在结肠和膀胱之间交叉致敏中的作用。具体目标旨在对所提出的假设进行全面评估。特异性目的1将确定结肠炎症是否会改变膀胱DRG神经元在树脂干扰素（RTX）对感觉传入神经脱敏前后的兴奋性。并探讨RTX对胸腰椎和腰骶部DRG神经元中TRPV1、CGRP和SP表达的影响。特异性目标2将关注辣椒素敏感的C-和adelta纤维在伤害性结肠传入输入到脊髓的会聚和膀胱神经元的加工中的作用。特异性目的3将验证结肠或膀胱感觉纤维的脱敏可以防止实验性结肠炎后神经源性膀胱的发展。我们相信，揭示这些机制将导致新的治疗方案的发展，可用于减轻慢性盆腔疼痛患者的泌尿生殖系统和胃肠道疾病。公共卫生相关性：本项目将研究盆腔器官间交叉致敏的神经体液机制，揭示其与盆腔神经源性炎症和慢性盆腔疼痛发生的关系。这些机制的发现将导致新的治疗方案的发展，可用于减轻慢性盆腔疼痛患者的泌尿生殖系统和胃肠道疾病。

DESCRIPTION: Chronic pelvic pain is a common symptom of many urologic and gastrointestinal disorders including interstitial cystitis and irritable bowel syndrome. Cross-sensitization among pelvic organs contributes to chronic pelvic pain of unknown etiology. Our long term goal is to elucidate the neural, neurohumoral and neuroimmune mechanisms underlying cross-sensitization in the pelvis and reveal its correlation with the occurrence of neurogenic inflammation and chronic pelvic pain. Recent studies demonstrated the role of sensory afferent pathways in pelvic organ cross-sensitization, however, our understanding of the underlying mechanisms is still rudimentary. We hypothesize that colonic inflammation alters the function of the urinary bladder due to sensitization of afferent sensory pathways in the spinal cord and dorsal root ganglia (DRG). We suggest that enhanced excitability of sensory neurons in the DRG and spinal cord induced by colonic inflammation alters the expression of pro-inflammatory neuropeptides as well as their release in the urinary bladder, leading to the development of neurogenic inflammation in the latter. Neuroanatomical, immunohistochemical, electrophysiological and neuropharmacological studies will be carried out to characterize the role of sensory neural pathways in cross-sensitization between the colon and urinary bladder. The specific aims are designed to provide a comprehensive assessment of the proposed hypothesis. Specific Aim 1 will determine whether colonic inflammation alters the excitability of bladder DRG neurons before and after desensitization of sensory afferents with resiniferatoxin (RTX). It will also address the effects of RTX treatment on the expression of TRPV1, CGRP and SP in thoracolumbar and lumbosacral DRG neurons. Specific Aim 2 will focus on the role of capsaicin-sensitive C- and Adelta-fibers in the processing of nociceptive colonic afferent input to convergent and bladder neurons in the spinal cord. Specific Aim 3 will test the hypothesis that desensitization of sensory fibers in the colon or urinary bladder prevents the development of a neurogenic bladder after experimentally induced colitis. We believe that uncovering these mechanisms will lead to the development of new therapeutic protocols that can be used to alleviate chronic pelvic pain in patients with genitourinary and gastrointestinal disorders. PUBLIC HEALTH RELEVANCE: This project will study the neurohumoral mechanisms underlying the cross-sensitization among pelvic organs and reveal its correlation with the occurrence of neurogenic inflammation in the pelvis and chronic pelvic pain. Uncovering of these mechanisms will lead to the development of new therapeutic protocols that can be used to alleviate the chronic pelvic pain in patients with genitourinary and gastrointestinal disorders.