Peripheral Contributions to Bladder Hypersensitivity

膀胱感觉障碍多见于间质性膀胱炎、膀胱出口 梗阻和膀胱过度活动，包括特发性逼尿肌不稳定，以疼痛和 不适和对刺激(即膀胱过敏)的敏感度增强。炎症存在于 例如，许多(但不是所有)主要的膀胱疾病和间质性膀胱炎通常表现为 可证明的器质性原因(即，没有明显的机械、生化或炎症条件 解释症状)。因此，内脏过敏可能不同于躯体痛觉过敏，后者通常是 与组织损伤和炎症有关。因为神经和神经的解剖组织 对于内脏来说，足够的伤害性刺激不同于神经支配和足够的伤害性刺激 躯体领域，内脏高敏感的外周机制不同于躯体痛觉过敏 而且还没有被很好地理解。该研究计划的长期目标是了解外围设备 膀胱过敏症的发病机制。 目前的应用建议在之前建立刺激和治疗的功能相关性 随后检查外周对膀胱过敏症发展的影响。这个 要检查的与膀胱过敏有关的外周受体包括ASIC3、TRPV1、 P2X2-3和PAR2，所有这些都与内脏高敏感性有关。对于这些受体中的每个， 在正常和过敏性条件下(例如，环磷酰胺引起的膀胱炎)，我们将研究：1)它们 膀胱排尿和反射排尿对功能评价膀胱过敏的贡献，2) 膀胱内盆神经和腰内脏神经纤维末梢的力学和化学敏感性 使用体外膀胱神经制剂，以及3)膀胱感觉的全细胞电流和兴奋性 神经元，通过逆行示踪剂的含量进行鉴定。总体假设是这四种配基门控离子 在膀胱中，经络起到机械转导作用。我们还假设质子 和/或内源性介质(如三磷酸腺苷、肥大细胞类胰蛋白酶)导致膀胱过敏，并可 即使在没有直接组织损伤的情况下也要这样做，这与间质性膀胱炎和其他所谓的 “功能性”内脏疾病。

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.