Peripheral Contributions to Bladder Hypersensitivity

描述(申请人提供)：许多膀胱感觉障碍，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主要的膀胱疾病和间质性膀胱炎中，例如，通常没有可证明的器质性原因(即没有明显的机械、生化或炎症条件来解释这些症状)。因此，内脏过敏可能不同于躯体痛觉过敏，后者通常与组织损伤和炎症有关。由于内脏神经的解剖组织和对内脏的足够伤害性刺激不同于躯体领域的神经支配和足够的伤害性刺激，内脏高敏感性的外周机制不同于躯体痛觉过敏，因此人们对内脏高敏感症的外周机制尚不清楚。该研究计划的长期目标是了解膀胱过敏的外周机制。目前的应用建议在随后检查外周对膀胱过敏发展的贡献之前，建立刺激和治疗的功能相关性。需要研究的外周受体包括ASIC3、TRPV1、P2X2-3和PAR2，所有这些受体都与内脏高敏感性有关。对于这些受体中的每一种，在正常和超敏条件下(例如，环磷酰胺诱导的膀胱炎)，我们将研究：1)它们在膀胱排尿和反射排尿中的作用，以功能评估膀胱的超敏反应；2)使用体外膀胱神经制剂对膀胱中的盆神经和腰内脏神经纤维终末的机械和化学敏感性；以及3)通过逆行示踪剂含量确定的膀胱感觉神经元的全细胞电流和兴奋性。总的假设是，这四个离子通道参与了膀胱的机械转导。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)与膀胱过敏有关，而且即使在没有直接的组织损伤的情况下也可以这样做，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.