Peripheral Contributions to Bladder Hypersensitivity

描述（由申请人提供）：在间质性膀胱炎、膀胱出口梗阻和膀胱过度活动中常见的许多膀胱感觉障碍，包括特发性逼尿肌不稳定，其特征在于疼痛和不适以及对刺激的敏感性增强（即，膀胱过敏）。炎症存在于许多但不是所有的主要膀胱疾病和间质性膀胱炎中，例如，经常在没有可证实的器质性原因的情况下出现（即，没有明显的机械、生物化学或炎症状况来解释症状）。因此，内脏超敏反应可以不同于通常与组织损伤和炎症相关的躯体痛觉过敏。由于内脏的神经支配和足够的伤害性刺激的解剖组织与躯体领域的神经支配和足够的伤害性刺激不同，内脏高敏感性的外周机制不同于躯体痛觉过敏，并且还没有得到很好的理解。这项研究计划的长期目标是了解膀胱超敏反应的外周机制。本申请提出在随后检查外周对膀胱超敏反应的发展的贡献之前建立刺激和治疗的功能相关性。要检查的对膀胱超敏性的贡献的外周受体包括ASIC 3、TRPV 1、P2 X 2 -3和PAR 2，所有这些都与内脏超敏性有关。对于这些受体中的每一种，在正常和过敏条件下（例如，环磷酰胺诱导的膀胱炎），我们将研究：1）它们对膀胱排尿和反射排尿的贡献以功能性地评估膀胱超敏性，2）使用体外膀胱神经制备物的膀胱中骨盆神经和腰内脏神经纤维末梢的机械和化学敏感性，和3）通过逆行示踪剂的含量鉴定的膀胱感觉神经元的全细胞电流和兴奋性。总体假设是这四种配体门控离子通道有助于膀胱中的机械转导。我们还假设质子和/或内源性介质（例如，ATP，肥大细胞类胰蛋白酶）导致膀胱超敏反应，甚至在没有明显组织损伤的情况下也会这样做，这与间质性膀胱炎和其他所谓的“功能性”内脏疾病有关。

DESCRIPTION (provided by applicant): Many disorders of urinary bladder sensation, which is common in interstitial cystitis, bladder outlet obstruction, and bladder over activity, including idiopathic detrussor instability, are characterized by pain and discomfort and enhanced sensitivity to stimuli (i.e., bladder hypersensitivity). Inflammation is present in many, but not all major bladder disorders and interstitial cystitis, for example, often presents without demonstrable organic cause (i.e., there is no apparent mechanical, biochemical or inflammatory condition to explain the symptoms). Visceral hypersensitivity thus can differ from somatic hyperalgesia, which is typically associated with tissue injury and inflammation. Because the anatomical organization of innervation and adequate noxious stimuli for the viscera are unlike the innervation and adequate noxious stimuli in the somatic realm, peripheral mechanisms of visceral hypersensitivity differ from those of somatic hyperalgesia and are not well understood. The long term objective of this research program is to understand peripheral mechanisms of bladder hypersensitivity. The current application proposes to establish functional relevance of stimuli and treatments before subsequent examination of peripheral contributions to the development of bladder hypersensitivity. The peripheral receptors to be examined for contributions to bladder hypersensitivity include ASIC3, TRPV1, P2X2-3 and PAR2, all of which have been implicated in visceral hypersensitivity. For each of these receptors, in normal and hypersensitive conditions (e.g., cyclophosphamide-induced cystitis), we will study: 1) their contribution to bladder voiding and reflex micturition to functionally evaluate bladder hypersensitivity, 2) mechano- and chemo-sensitivity of pelvic nerve and lumbar splanchnic nerve fiber terminals in the bladder using an in vitro bladder-nerve preparation, and 3) whole cell currents and excitability of bladder sensory neurons, identified by content of retrograde tracer. The overall hypothesis is that these four lig and-gated ion channels contribute to mechano-transduction in the urinary bladder. We also hypothesize that protons and/or endogenous mediators (e.g., ATP, mast cell tryptase) contribute to bladder hypersensitivity and can do so even in the absence of frank tissue damage, which is relevant to interstitial cystitis and other so-called "functional" visceral disorders.