Afferent Mechanisms of Pelvic Hypersensitivity

描述（由申请人提供）：患有慢性腹部和盆腔疼痛疾病的患者在胃肠科医生、泌尿科医生和妇科医生那里寻求缓解的患者中占很大比例。两种常见的盆腔疾病，膀胱疼痛综合征（PBS）和肠易激综合征（IBS），其特征是膀胱/排便习惯改变（例如，尿急、尿频，肠易激综合征中大便一致性）、疼痛和过敏。这些患者通常表现出明显较低的刺激反应阈值（例如，膀胱术，直肠膨胀），抱怨在正常器官功能期间敏感性增加，并且在躯体转诊区域表现出压痛增加，此外，体积扩大。有趣的是，PBS和IBS在没有明显的病理生物学原因的情况下存在，因此被定性为“功能性”。人们普遍认为功能障碍反映了中枢神经系统加工的改变，但大量证据表明，持续的传入驱动显著地导致了复发性的、无法解释的疼痛和超敏反应。本建议的目的是确定疼痛和超敏反应产生的机制，并将其作为制定更明智和更成功的管理策略的必要步骤。目的1：在膀胱和结直肠的腰椎内脏神经和盆腔神经的电生理实验中，表征机械敏感和不敏感传入神经的比例。7目的2：在行为实验中评估器官超敏反应，然后在超敏小鼠膀胱和结直肠中测定膀胱和结直肠机械不敏感传入神经（MIAs）的比例。我们假设，与正常对照相比，过敏小鼠器官中mia的比例将显著降低。目的3：确定机械敏感和不敏感的膀胱和结肠背根神经节神经元在腰椎和盆腔神经通路中的“化学型”。我们假设mia和机械敏感传入神经之间、不同机械敏感传入神经之间以及器官之间的化学型存在显著差异。

DESCRIPTION (provided by applicant): Persons with chronic abdominal and pelvic pain disorders comprise a large proportion of patients seeking relief from gastroenterologists, urologists and gynecologists. Two common pelvic disorders, painful bladder syndrome (PBS) and irritable bowel syndrome (IBS), are characterized by altered bladder/bowel habits (e.g., urge, frequency and, in IBS, stool consistency), pain and hypersensitivity. These patients typically exhibit significantly lower response thresholds to provocative stimuli (e.g., cystometry, rectal distension), complain of increased sensitivity during normal organ function, and exhibit increased tenderness in areas of somatic referral which, in addition, are expanded in size. Interestingly, PBS and IBS exist in the absence of an apparent pathobiological cause and are thus characterized as 'functional.' It is widely assumed that functional disorders reflect altered CNS processing, but considerable evidence suggests that persistent afferent drive contributes significantly to the recurrent, unexplained pain and hypersensitivity that characterize them. The objective of this proposal is to determine the mechanisms by which pain and hypersensitivity arise and is maintained as a necessary step in developing better informed and more successful management strategies. The Aims include: 7 Aim 1: characterize the proportions of mechano-sensitive and insensitive afferents in electrophysiological experiments in the both the lumbar splanchnic and pelvic nerve innervations of the bladder and colorectum. 7 Aim 2: evaluate organ hypersensitivity in behavioral experiments, after which the proportions of bladder and colorectal mechanically insensitive afferents (MIAs) will be determined in bladder and colorectum removed from hypersensitive mice. We hypothesize the proportions of MIAs will be significantly reduced in organs from hypersensitive mice relative to normal controls. 7 Aim 3: identify the 'chemotypes' of mechano-sensitive and insensitive bladder and colorectal dorsal root ganglion neurons in both the lumbar splanchnic and pelvic nerve pathways. We hypothesize that there are significant differences in chemotype between MIAs and mechanosensitive afferents as well as between different mechanosensitive afferents and, further, between organs.