Early-In-Life Inflammation Effects on Urinary Bladder Sensation

生命早期炎症对膀胱感觉的影响

• 批准号: 7417783
• 负责人: ALAN RANDICH
• 金额: $ 21.32万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-05 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7417783
• 关键词: Accounting; Address; Adolescent; Adult; Appendix; Bladder; Bladder Tissue; Blood Pressure; CALCA gene; Calcitonin Gene-Related Peptide; Classification; Data; Development; Disease; Equus caballus; Esthesia; Estrous Cycle; Etiology; Event; Exposure to; FOS gene; Female; Frequencies; Functional disorder; Funding; Gene Proteins; Grant; Histopathology; Hypersensitivity; Immunohistochemistry; Individual; Inflammation; Inflammatory; Interstitial Cystitis; Label; Life; Life Experience; Measures; Micturition Reflex; Modality; National Institute of Diabetes and Digestive and Kidney Diseases; Neonatal; Neurons; Nociception; Nociceptive Reflex; Nociceptive Stimulus; Outcome; Pain; Patients; Pelvis; Peripheral; Peroxidase; Peroxidases; Phenotype; Predisposition; Process; Radish; Rattus; Reflex action; Reporting; Research Personnel; Response to stimulus physiology; S100A12 gene; Sensory; Spinal; Spinal Cord; Standards of Weights and Measures; Stimulus; Structure; Substance P; Symptoms; TRPV1 gene; Testing; Translations; Urinary tract infection; Urination; Wheat Germ Agglutinins; base; density; early experience; experience; gastrointestinal system; human S100A12 protein; innovation; intravesical; neonatal exposure; neurochemistry; neurophysiology; nociceptive response; novel therapeutics; painful bladder syndrome; pressure; programs; response; spinal reflex; urinary

DESCRIPTION (provided by applicant): Early-in-life exposure to painful and/or inflammatory stimuli can produce permanent changes in the neuroanatomical and neurophysiological substrates that process nociceptive stimuli in both somatic and gastrointestinal systems. We propose that early-in-life bladder inflammation also may predispose an individual to experience increased bladder sensitivity as an adult. As part of an NIDDK-funded R21 grant, preliminary studies showed that neonatal, but not adolescent, exposure to bladder inflammation led to a hypersensitive nociceptive and reflex state in female rats raised to adulthood, as manifested by increased visceromotor reflexes (VMRs) and arterial blood pressure (ABP) responses to phasic urinary bladder distention (UBD), decreased threshold for micturition reflexes in cystometrographic (CMC) analyses, and increased baseline frequency of micturition. These outcomes also are consistent with two primary symptoms of the painful bladder syndrome interstitial cystitis (IC): enhanced sensory (pain-urgency) and reflex responses (i.e., reduced bladder capacity) to bladder distention. These data served to generate the overall hypothesis of the present proposal. Specifically, we propose the following: An alteration in neuronal sensory substrates is initiated by early-in-life bladder inflammation. This process enhances susceptibility to the development of a hypersensitive state as an adult, especially when a second bladder insult occurs, and is manifested by lowered intravesical pressure thresholds for micturition reflexes and enhanced bladder-related nociceptive responses. This results in urinary dysfunction and pathological urinary bladder pain as an adult. The general hypothesis is tested in three specific aims that determine in a quantitative fashion the effect of neonatal, and in some cases adolescent, bladder inflammation on: (1) VMRs and c-fos expression to phasic UBD, baseline micturition frequency, and micturition reflexes in CMG tests of adult rats, (2) the structure of the bladder, and the density and spinal distribution of bladder afferents in studies of histopathology using protein gene product 9.5 (PGP 9.5), wheat germ agglutinin horse-radish peroxidase (WGA-HRP), substance P, CGRP, and TRPV1 immunhistochemisty, and (3) responses of C- and A-5 bladder afferents to phasic UBD in adult rats. We believe these systematic studies, based on an innovative hypothesis, will lay the groundwork for potential novel therapeutic modalities for the treatment of urinary bladder pain by identifying the substrates for the development of bladder hypersensitivity. Translation to the treatment of painful bladder syndromes like 1C would be highly probable.

描述（由申请人提供）：生命早期暴露于疼痛和/或炎症刺激可以在躯体和胃肠道系统中处理伤害性刺激的神经解剖和神经生理基质中产生永久性变化。我们认为，生命早期的膀胱炎症也可能使个体在成年后膀胱敏感性增加。作为niddp资助的R21基金的一部分，初步研究表明，新生儿（而非青少年）暴露于膀胱炎症导致成年雌性大鼠的超敏感伤害感受和反射状态，表现为内脏运动反射（VMRs）和动脉血压（ABP）对相膀胱膨胀（UBD）的反应增加，膀胱造影（CMC）分析中排尿反射阈值降低，以及基线排尿频率增加。这些结果也与膀胱疼痛综合征间质性膀胱炎（IC）的两个主要症状相一致：对膀胱膨胀的感觉（疼痛急迫性）和反射反应（即膀胱容量减少）增强。这些数据有助于产生本建议的总体假设。具体来说，我们提出以下建议：神经感觉基质的改变是由生命早期膀胱炎症引起的。这一过程增加了成人发展为超敏状态的易感性，特别是当发生第二次膀胱损伤时，表现为排尿反射膀胱内压力阈值降低和膀胱相关伤害反应增强。这导致尿功能障碍和病理性膀胱疼痛作为一个成年人。一般假设在三个具体目标中得到检验，这些目标以定量的方式确定新生儿和某些情况下青少年膀胱炎症对以下方面的影响：(1)成年大鼠CMG试验中VMRs和C- fos对期相UBD的表达、基线排尿频率和排尿反射；(2)组织病理学中蛋白基因产物9.5 （PGP 9.5）、小麦胚集素马胡萝卜过氧化酶（WGA-HRP）、P物质、CGRP和TRPV1免疫组织化学研究膀胱结构、膀胱传入神经密度和脊髓分布；(3)成年大鼠C-和A-5膀胱传入神经对期相UBD的反应。我们相信这些基于创新假设的系统研究，将通过确定膀胱超敏反应发展的底物，为潜在的治疗膀胱疼痛的新治疗方式奠定基础。很有可能将其转化为治疗1C型膀胱疼痛综合征。