PERIPHERAL CONTRIBUTIONS TO BLADDER HYPERSENSITIVITY

描述（由申请方提供）：膀胱感觉障碍（不适、疼痛和敏感性增加）表征疼痛性膀胱综合征/间质性膀胱炎（PBS/IC）。PBS/IC是一种慢性和使人衰弱的疾病，其中尿频和尿急与膀胱体积小相关。然而，疼痛是PBS/IC患者中最常见和最令人不安的症状，并且通常是内脏疼痛的典型症状-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受试者中的尿动力学研究证实，在较低的膀胱内体积下感知膀胱感觉和充盈，导致正常心理物理功能的急剧变化（即，膀胱过敏）。由于内脏神经支配是独特的（器官由两条神经支配），并且有害的内脏刺激与有害的组织损伤性躯体刺激不同，因此膀胱超敏反应的外周机制与躯体痛觉过敏的机制不同。膀胱的机械和/或化学超敏反应在很大程度上是PBS/IC患者所经历的疼痛和不适的基础，但赋予膀胱感觉神经元的机械敏感性和/或致敏性的分子和介质及其对膀胱疼痛的贡献知之甚少。 离子通道TRPV 1和P2 X3与膀胱超敏反应有关。我们假设TRPV 1和P2 X3有助于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）使用膀胱测压法功能性地评价膀胱超敏性，2）使用体外膀胱神经制备物对膀胱中骨盆神经和腰内脏神经感受末梢的机械和化学敏感性，（3）膀胱感觉神经元的全细胞电流和兴奋性，通过逆行示踪剂的含量鉴定。 公共卫生相关性：相关性：间质性膀胱炎（IC）是一种慢性和使人衰弱的疾病，最常见于女性，其中疼痛是最常见和最令人不安的症状。IC是一种高度敏感的疾病，很难控制。本研究的目的是确定IC疼痛产生和维持的机制，作为制定更明智和更成功的管理策略的第一步。

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. PUBLIC HEALTH RELEVANCE: Relevance: Interstitial cystitis (IC) is a chronic and debilitating disorder, most common in women, and in which pain is the most common and most troubling symptom. IC represents a hypersensitive condition and is difficult to manage. The objective of this research is to determine the mechanisms by which the pain in IC arises and is maintained as a first step in developing better informed and more successful management strategies.