Cross-sensitization in the pelvis and neurogenic bladder

描述：慢性盆腔疼痛是许多泌尿外科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。盆腔器官之间的交叉敏感化导致原因不明的慢性盆腔疼痛。我们的长期目标是阐明骨盆交叉敏化的神经、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盆腔疼痛的发生的相关性。最近的研究证实了感觉传入通路在盆腔器官交叉敏化中的作用，然而，我们对其潜在机制的了解仍然很少。我们假设结肠炎改变了膀胱的功能，这是由于脊髓和背根神经节(DRG)的传入感觉通路敏化所致。我们认为，结肠炎引起的背根节和脊髓感觉神经元兴奋性的增强改变了促炎神经肽的表达及其在膀胱中的释放，从而导致后者神经源性炎症的发生。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敏化中的作用。这些具体目标旨在为所提出的假设提供一个全面的评估。具体目标1将确定在用树脂毒素(RTX)脱敏感觉神经传入前后，结肠炎是否改变膀胱DRG神经元的兴奋性。它还将探讨RTX治疗对胸腰段和腰椎背根神经节神经元TRPV1、CGRP和SP表达的影响。具体目标2将集中在辣椒素敏感的C和ADelta纤维在处理伤害性结肠传入到脊髓会聚神经元和膀胱神经元的过程中的作用。具体目标3将测试这一假说，即在实验诱导的结肠炎后，结肠或膀胱中感觉纤维的脱敏可以防止神经源性膀胱的发展。我们相信，揭示这些机制将导致开发新的治疗方案，可用于缓解患有泌尿生殖系统和胃肠道疾病的患者的慢性盆腔疼痛。公共卫生相关性：该项目将研究盆腔器官之间交叉敏感化的神经体液机制，并揭示其与骨盆神经源性炎症和慢性盆腔疼痛的发生的相关性。这些机制的发现将导致开发新的治疗方案，可用于缓解泌尿生殖系统和胃肠道疾病患者的慢性盆腔疼痛。

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.