Effects of early-in-life bladder stimulation on adults

生命早期膀胱刺激对成年人的影响

• 批准号: 6710389
• 负责人: ALAN RANDICH
• 金额: $ 14.5万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6710389
• 关键词: age difference; behavioral /social science research tag; early experience; hyperalgesia; infant animal; inflammation; juvenile animal; laboratory rat; mature animal; pain threshold; urinary bladder disorder

DESCRIPTION (provided by applicant): Pain originating from the urinary bladder is a common clinical entity affecting more than 50% of females at some time in their lives. Some conditions are easy to treat, but others, such as interstitial cystitis (IC) have proven resistant to diagnosis and treatment. There are multiple proposed etiologies for IC with the common theme of an eventual sensitization/activation of sensory elements: abnormalities in the periphery lead to central neurophysiological changes that become expressed as enhanced sensory (pain-urgency) and reflex responses (i.e. reduced bladder capacity) which may outlast "triggering" events within the bladder. In somatic systems, it has been demonstrated that exposure to painful stimuli during early life can produce permanent changes in the neuroanatomical and neurophysiological substrates that process nociceptive information. Since 10-28% of adult patients with IC report urinary bladder symptoms as children a logical avenue for exploration is an examination of the effects of early-in-life painful bladder experiences on bladder responses in adults since individuals who are "primed" for hypersensitivity of the bladder could have pain that is both easily triggered and manifested as a sustained response to normally self-limited events. The hypothesis central to these studies is: A peripheral and spinal neuronal sensitization process initiated by early-in-life, high-intensity primary afferent activation, can enhance susceptibility to pathological urinary bladder pain as an adult. This early-in-life process leads to a hypersensitive state that is manifested by lowered intravesical stimulus thresholds needed for pain evocation and augmented responses to supra-threshold stimuli. To test this hypothesis reflex, primary afferent neuronal and spinal neuronal responses to urinary bladder distension (UBD) will be characterized in rats, which are given high-intensity UBD and/or inflammatory stimuli (intravesical zymosan) in the neonatal, pre-pubescent or post-pubescent periods. These exploratory studies will lay the groundwork for potential, novel therapeutic modalities for the treatment of urinary bladder pain by identifying substrates of hypersensitivity development and thereby treatment of urinary bladder pain by identifying substrates of hypersensitivity development and thereby presenting targets for intervention. Translation to the treatment of IC would be highly probable.

描述（由申请人提供）：源自膀胱的疼痛是一种常见的临床实体，影响50%以上的女性在其一生中的某个时间。有些情况很容易治疗，但其他情况，如间质性膀胱炎（IC）已被证明对诊断和治疗有抵抗力。IC有多种病因，其共同主题是感觉元件的最终致敏/激活：外周异常导致中枢神经生理学变化，表现为增强的感觉（疼痛-紧迫感）和反射反应（即膀胱容量降低），其持续时间可能超过膀胱内的“触发”事件。在躯体系统中，已经证明，在生命早期暴露于疼痛刺激可以在处理伤害性信息的神经解剖学和神经生理学基底中产生永久性变化。由于10-28%的IC成人患者在儿童时报告膀胱症状，因此合理的探索途径是检查生命早期膀胱疼痛经历对成人膀胱反应的影响，因为膀胱超敏反应“启动”的个体可能具有容易触发并表现为对正常自限性事件的持续反应的疼痛。这些研究的核心假设是： 由生命早期高强度初级传入激活启动的外周和脊髓神经元敏化过程可以增强成年后对病理性膀胱疼痛的易感性。这种生命早期过程导致过敏状态，表现为疼痛诱发所需的膀胱内刺激阈值降低和对阈上刺激的反应增强。 为了测试该假设反射，将在大鼠中表征对膀胱扩张（UBD）的初级传入神经元和脊髓神经元反应，所述大鼠在新生儿、青春期前或青春期后给予高强度UBD和/或炎性刺激（膀胱内酵母聚糖）。这些探索性研究将为通过识别超敏反应发生的底物来治疗膀胱疼痛的潜在新型治疗方式奠定基础，从而通过识别超敏反应发生的底物来治疗膀胱疼痛，从而提出干预目标。转化为IC的治疗将是非常可能的。