Cross-sensitization between the bladder and colon

描述（由申请人提供）：病因不明的慢性盆腔疼痛是一种常见疾病，尤其是女性。据文献记载，与健康对照相比，患有胃肠道疾病（包括肠易激综合征（IBS）和炎性肠病（IBD））的患者经常抱怨泌尿系统症状，例如尿失禁、排尿频率和急迫性。这可能是结肠和膀胱之间交叉致敏的结果。在这个探索性的建议中，我们试图定义结肠超敏反应模型中神经处理和膀胱平滑肌功能的变化。初步研究表明，存在会聚前脊髓神经元，接受来自膀胱和结肠的输入。具体目标1是确定在用TNBS滴注的急性结肠炎症后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。将通过测量内脏反射检查恢复状态下的结肠超敏反应。L 6-S2腰骶区域的背根神经节（DRG）中的细胞体将用注射到结肠和膀胱中的示踪染料逆行标记。将使用膜片钳技术在膀胱和结肠的经鉴定的DRG细胞以及共标记的DRG细胞中测定细胞兴奋性。具体目标2将是确定脊髓神经元的性质的变化，证明膀胱和结肠之间的收敛。在这个目标中，我们将确定调制的阈值敏感性和持续时间的冲动，结肠炎症和以下恢复。具体目标3将是确定结肠炎症和无明显结肠炎症的过敏状态期间膀胱平滑肌的变化。我们将测量逼尿肌肌条的收缩性和促炎细胞因子mRNA的变化。这些研究的结果将允许制定关于膀胱和结肠之间交叉致敏的神经处理和分子变化的假设。

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.