Cross-sensitization between the bladder and colon

描述(申请人提供)：原因不明的慢性盆腔疼痛是一种常见的疾病，尤其是在女性。已有文献证明，与健康对照组相比，患有肠易激综合征(IBS)和炎症性肠病(IBD)等胃肠道疾病的患者经常主诉尿失禁、尿频和尿急等尿路症状。这可能是结肠和膀胱之间交叉敏感的结果。在这个探索性的方案中，我们试图定义结肠高敏感性模型中神经处理和膀胱平滑肌功能的变化。初步研究表明，存在汇聚的脊髓前神经元，它们接受来自膀胱和结肠的输入。具体目的1是确定急性结肠炎后注入TNBS和恢复后这些初级感觉神经元的电兴奋性和离子电流的变化。恢复状态下的结肠过敏将通过测量内脏运动反射来检查。L6-S2腰骶段背根神经节(DRG)的细胞体将被注入结肠和膀胱内的示踪染料逆行标记。细胞的兴奋性将使用膜片钳技术在已识别的膀胱和结肠的DRG细胞以及那些共同标记的细胞中确定。具体目标2将是确定显示膀胱和结肠之间会聚的脊髓神经元特性的变化。在这一目标中，我们将确定结肠炎症和随后的恢复对阈值敏感性和冲动持续时间的调节。具体目标3将确定结肠炎和无明显结肠炎的过敏状态下膀胱平滑肌的变化。我们将测量逼尿肌条的收缩能力和促炎细胞因子的mRNA的变化。这些研究的发现将允许提出关于膀胱和结肠之间的神经处理和交叉敏化的分子变化的假说。

DESCRIPTION (provided by applicant): Chronic pelvic pain of unknown etiology is a common disorder, particularly in women. It has been documented that compared to healthy controls, patients with gastrointestinal diseases including irritable bowel syndrome (IBS) and inflammatory bowel diseases (IBD) often complain of urinary symptoms such as nocturia, frequency and urgency of micturition. This may be the result of cross-sensitization between the colon and bladder. In this exploratory proposal we seek to define the changes in the neural processing and bladder smooth muscle function in a model of colonic hypersensitivity. Preliminary studies indicate the presence of convergent pre-spinal neurons that receive input from both the bladder and colon. Specific Aim 1 is to determine the changes in electrical excitability and the ionic currents of these primary sensory neurons following acute colonic inflammation with TNBS instillation and after recovery. Colonic hypersensitivity in the recovery state will be examined by measuring the visceromotor reflex. Cell bodies in the dorsal root ganglia (DRG) of the L6-S2 lumbosacral region will be retrogradely labeled with tracer dyes injected into the colon and bladder. Cell excitability will be determined using patch-clamp techniques in identified DRG cells of the bladder and colon and those that co-label. Specific Aim 2 will be to determine the changes in the properties of spinal neurons that demonstrate convergence between the bladder and colon. In this aim, we will determine the modulation of the threshold sensitivity and duration of impulses by colonic inflammation and following recovery. Specific Aim 3 will be to identify the changes in the bladder smooth muscle by colonic inflammation and during hypersensitive state with no overt colonic inflammation. We will measure the contractility of detrusor muscle strips and changes in the mRNA of pro-inflammatory cytokines. The findings from these studies will allow for formulation of hypotheses regarding neural processing and molecular changes in cross-sensitization between the bladder and colon.