Preclinical phenotypic modeling of chronic urologic pelvic pain

项目概要/摘要 泌尿生殖器官和盆腔区域的超敏反应与泌尿系统慢性盆腔疼痛相关 综合征（UCPPS;包括间质性膀胱炎/膀胱疼痛综合征和慢性前列腺炎）。证据 从动物模型表明，中枢神经系统处理泌尿生殖器/骨盆感觉， 信息可以通过（i）在感觉发育期间发生的新生儿事件来单独修改， 永久改变神经解剖学基质，或（ii）经历的不良事件，如压力或创伤 在发育期或成年期。这两种现象都具有高度的临床相关性， 有充分的理由相信初级传入神经元的表型和功能的相应改变 神经支配泌尿生殖和骨盆区域对于超敏反应的发展至关重要，因此， 作为治疗干预的目标。这个项目的长期目标是系统地研究变化 在躯体和内脏泌尿生殖结构的初级传入脊髓感觉处理中， UCPPS相关动物模型。本提案的目的是系统地审查 新生儿膀胱炎（NBI）或母体分离（NMS），单独或与成人联合 同类损伤（膀胱再炎症，急性或慢性应激），泌尿生殖系统过敏和/或 广泛的疼痛。作为这一提议基础的指导假设是，经历早期生活 炎症或应激改变泌尿生殖初级传入和脊髓背角神经元的不同亚类 反过来，在继发性成人暴露于炎症的情况下，抑制或增强泌尿生殖系统的敏感性 或者压力这一假设将在三个特定的目标，使用：1）在体内反射行为，加上 分层神经元群体的光遗传学靶向以确定NBI或NMS如何改变初级传入- 驱动反射行为，2）膜片钳和细胞外体内电生理学来表征功能 NBI或NMS后泌尿生殖传入和脊髓背角神经元通路内的活动，以及3） 神经化学和光遗传学鉴定泌尿生殖系统中的神经化学介质和受体/转换器 组织、初级传入神经元和脊髓背角参与盆腔过敏的发展。

PROJECT SUMMARY/ABSTRACT Hypersensitivity of the urogenital organs and pelvic region is associated with urologic chronic pelvic pain syndrome (UCPPS; inclusive of interstitial cystitis/painful bladder syndrome and chronic prostatitis). Evidence from animal models demonstrates that central nervous system processing of urogenital/pelvic sensory information may be modified individually by (i) neonatal events that occur during sensory development and that permanently alter neuroanatomical substrates, or (ii) adverse events, such as stress or trauma, experienced during development or adulthood. Both of these phenomena have a high degree of clinical relevance, and there is good reason to believe that consequential alterations in the phenotype and function of primary afferent neurons innervating the urogenital and pelvic region are critical for the development of hypersensitivity and, thus, would serve as targets for therapeutic intervention. The long-term goal of this project is to systematically study changes in primary afferent-to-spinal cord sensory processing of somatic and visceral urogenital structures in clinically relevant animal models of UCPPS. The objective of the current proposal is to systematically examine the effects of neonatal bladder inflammation (NBI) or maternal separation (NMS), alone and in combination with an adult insult of the same class (bladder re-inflammation, acute or chronic stress), on urogenital hypersensitivity and/or widespread pain. The guiding hypothesis that serves as the basis of this proposal is that experiencing early life inflammation or stress alters distinct subclasses of urogenital primary afferent and spinal dorsal horn neurons that, in turn, inhibit or augment urogenital sensitivity in the context of a secondary adult exposure to inflammation or stress. This hypothesis will be addressed in three specific aims using: 1) in vivo reflex behaviors coupled with optogenetic targeting of stratified neuronal populations to determine how NBI or NMS alter primary afferent- driven reflex behaviors, 2) patch-clamp and extracellular in vivo electrophysiology to characterize functional activity within urogenital afferent and spinal dorsal horn neuronal pathways following NBI or NMS, and 3) neurochemistry and optogenetics to identify neurochemical mediators and receptors/transducers in urogenital tissues, primary afferent neurons, and spinal dorsal horn involved in the development of pelvic hypersensitivity.