Peripheral Contributions to Bladder Hypersensitivity

膀胱感觉的许多障碍，其中常见于间质性膀胱炎、膀胱出口 梗阻和膀胱过度活动，包括特发性逼尿肌不稳定，其特征是疼痛， 不适和对刺激的增强的敏感性（即，膀胱过敏）。炎症存在于 例如，许多但不是所有的主要膀胱疾病和间质性膀胱炎通常表现为 可证实的器质性原因（即，没有明显的机械、生物化学或炎症状况， 解释症状）。因此，内脏超敏反应可以不同于躯体痛觉过敏，躯体痛觉过敏通常是 与组织损伤和炎症有关。因为神经支配的解剖组织和 对内脏的足够的伤害性刺激不同于神经支配和对内脏的足够的伤害性刺激。 躯体领域，内脏高敏感性的外周机制不同于躯体痛觉过敏 并且没有被很好地理解。这项研究计划的长期目标是了解周边 膀胱超敏反应的机制。 本申请提出在治疗之前建立刺激和治疗的功能相关性。 随后检查外周对膀胱超敏反应发展的贡献。的 要检查对膀胱超敏性的贡献的外周受体包括ASIC 3，TRPV 1， P2 X2 -3和PAR 2，所有这些都与内脏高敏感性有关。对于这些受体中的每一个， 在正常和过敏的情况下（例如，环磷酰胺诱导的膀胱炎），我们将研究：1）他们的 对膀胱排尿和反射排尿的贡献，以在功能上评价膀胱超敏反应，2） 膀胱内盆神经和腰内脏神经纤维末梢的机械和化学敏感性 使用体外膀胱神经制备，和3）膀胱感觉神经的全细胞电流和兴奋性， 神经元，通过逆行示踪剂的含量鉴定。总的假设是，这四个配体门控离子 通道有助于膀胱中的机械传导。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）有助于膀胱超敏反应， 即使在没有明显的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”内脏紊乱

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 ligand-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.