Preclinical phenotypic modeling of chronic urologic pelvic pain

项目摘要/摘要 泌尿生殖器官和盆腔区域的过敏与泌尿系慢性盆腔疼痛相关 综合征(UCPPS；包括间质性膀胱炎/痛性膀胱综合征和慢性前列腺炎)。证据 从动物模型中证明了中枢神经系统对泌尿生殖/盆腔感觉的处理 信息可通过(I)在感觉发育期间发生的新生儿事件单独修改 永久性改变神经解剖基础，或(Ii)经历的不良事件，如压力或创伤 在发育或成年期。这两种现象都具有高度的临床相关性，而且 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 支配泌尿生殖和盆腔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 临床上躯体和内脏泌尿生殖系统结构的初级传入-脊髓感觉加工 UCPPS相关动物模型。目前提案的目标是系统地审查影响 新生儿膀胱炎(NBI)或母体分离(NMS)，单独或与成人合并 同一类别的侮辱(膀胱炎、急性或慢性应激)，对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性假设是，经历早期生活 炎症或应激改变泌尿生殖系统初级传入神经元和脊髓背角神经元的不同亚类 在继发性成人暴露于炎症的情况下，这反过来又抑制或增强了泌尿生殖系统的敏感性 或者是压力。这一假设将在三个具体目标中得到解决：1)体内反射行为与 光遗传靶向分层神经元群体以确定NBI或NMS如何改变初级传入- 驱动反射行为，2)膜片钳和在体细胞外电生理学表征功能 NBI或NMS后泌尿生殖系统传入神经通路和脊髓背角神经元通路的活动 神经化学和光遗传学用于鉴定泌尿生殖系统的神经化学介质和受体/转导 组织、初级传入神经元和脊髓背角参与了骨盆超敏反应的发展。

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.