Afferent Mechanisms of Pelvic Hypersensitivity

描述(申请人提供)：慢性腹痛和盆腔疼痛疾病患者占向胃肠科医生、泌尿科医生和妇科医生寻求缓解的患者的很大比例。两种常见的盆腔疾病，痛性膀胱综合征(PBS)和肠易激综合征(IBS)，其特征是膀胱/肠道习惯改变(例如，冲动、频率和在IBS中，大便一致性)、疼痛和过敏。这些患者通常对刺激性刺激(如膀胱测压、直肠扩张)表现出显著较低的反应阈值，抱怨在正常器官功能期间敏感性增加，并在躯体转诊区域表现出更多的压痛，此外，体表转诊区域的大小也扩大了。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，因此被描述为“功能性”。人们普遍认为功能性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反复出现的、原因不明的疼痛和高敏感症。这项建议的目的是确定疼痛和过敏产生的机制，并将其作为制定更知情和更成功的管理策略的必要步骤。研究目的包括：7、目的1：研究腰椎内脏神经和盆神经支配膀胱和结肠的电生理实验中机械敏感和机械不敏感传入的比例。7目的2：在行为学实验中评估器官超敏反应，然后测定超敏小鼠膀胱和结肠机械不敏感传入(MIA)的比例。我们假设，与正常对照组相比，超敏小鼠器官中MIA的比例将显著降低。7目的3：确定机械敏感和机械不敏感的膀胱和大肠背根神经节神经元在腰、内脏和盆腔神经通路中的“化学类型”。我们假设在MIA和机械敏感传入之间、不同的机械敏感传入之间以及器官之间存在显著的化学类型差异。

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.