PERIPHERAL CONTRIBUTIONS TO BLADDER HYPERSENSITIVITY

描述(由申请人提供)：以痛性膀胱综合征/间质性膀胱炎(PBS/IC)为特征的膀胱感觉障碍(不适、疼痛和敏感度增加)。PBS/IC是一种慢性和衰弱的疾病，其尿频和尿急与膀胱体积小有关。然而，疼痛是PBS/IC患者最常见和最令人担忧的症状，也是典型的内脏疼痛--PBS/IC数据库中94%的注册者报告疼痛涉及另一个骨盆区域。PBS/IC受试者的尿动力学研究证实，膀胱感觉和充盈感在较低的膀胱内容量时被感知，导致正常心理物理功能(即膀胱超敏反应)左移。由于内脏神经支配是独特的(器官由两条神经支配)，而伤害性内脏刺激不同于伤害性组织损伤的躯体刺激，因此膀胱过敏的外周机制不同于躯体痛觉过敏。膀胱的机械和/或化学超敏反应在很大程度上是PBS/IC患者疼痛和不适的基础，然而，赋予膀胱感觉神经元机械敏感性和/或敏化的分子和介质及其在膀胱痛中的作用尚不清楚。离子通道TRPV1和P2X3参与了膀胱超敏反应。我们假设TRPV1和P2X3参与了膀胱神经支配的机械转导和/或敏化，我们将研究它们的贡献：1)使用膀胱测速仪从功能上评估膀胱超敏反应；2)使用体外膀胱神经制备方法对膀胱内的盆神经和腰内脏神经感受性终末进行机械和化学敏感性；以及3)通过逆行示踪剂含量确定其对膀胱感觉神经元的全细胞电流和兴奋性的影响。

DESCRIPTION (provided by applicant): Disorders of urinary bladder sensation (discomfort, pain and increased sensitivity) characterize painful bladder syndrome/interstitial cystitis (PBS/IC). PBS/IC is a chronic and debilitating disorder in which urinary frequency and urgency are associated with small bladder volume. Pain, however, is the most common and most troubling symptom in PBS/IC patients and is typical of visceral pain in general - 94% of registrants in a PBS/IC database report pain referred to another pelvic area. Urodynamic studies in PBS/IC subjects confirm that bladder sensations and fullness are perceived at lower intravesical volumes, resulting in a leftward shift of the normal psychophysical function (i.e., bladder hypersensitivity). Because the visceral innervation is unique (organs are innervated by two nerves) and noxious visceral stimuli are unlike noxious tissue-damaging somatic stimuli, peripheral mechanisms of bladder hypersensitivity differ from those of somatic hyperalgesia. Mechanical and/or chemical hypersensitivity of the bladder largely underlies the pain and discomfort experienced by PBS/IC patients, yet the molecules and mediators that confer mechanosensitivity and/or sensitization of bladder sensory neurons and their contribution to urinary bladder pain are poorly understood. The ion channels TRPV1 and P2X3 have been implicated in bladder hypersensitivity. We hypothesize that TRPV1 and P2X3 contribute to mechanotransduction and/or sensitization of the bladder innervation and we will study their contributions: 1) using cystometry to functionally evaluate bladder hypersensitivity, 2) to mechano- and chemo-sensitivity of pelvic nerve and lumbar splanchnic nerve receptive endings in the bladder using an in vitro bladder-nerve preparation, and 3) to whole cell currents and excitability of bladder sensory neurons, identified by content of retrograde tracer.