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中有很大一部分是寻求胃肠科医生、泌尿科医生和妇科医生缓解的患者。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），其特征在于改变的膀胱/肠道习惯（例如，急迫性、频率和IBS中的大便粘稠度）、疼痛和超敏反应。这些患者通常对刺激性刺激表现出显著较低的反应阈值（例如，膀胱测压、直肠扩张），抱怨在正常器官功能期间敏感性增加，并且在躯体参照区域表现出增加的压痛，此外，所述躯体参照区域在尺寸上扩大。有趣的是，PBS和IBS在没有明显病理生物学原因的情况下存在，因此被表征为“功能性的”。“人们普遍认为，功能性疾病反映了中枢神经系统处理的改变，但大量证据表明，持续的传入驱动对反复发作的、无法解释的疼痛和超敏反应有显著影响。本提案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。这些目标包括：7目标1：在膀胱和结肠直肠的腰内脏神经和盆神经支配的电生理实验中表征机械敏感和不敏感传入的比例。7目标2：在行为实验中评估器官超敏性，之后将在从超敏小鼠移除的膀胱和结肠直肠中确定膀胱和结肠直肠机械不敏感传入（MIA）的比例。我们假设相对于正常对照，过敏小鼠器官中MIA的比例将显著降低。7目标3：在腰内脏神经和骨盆神经通路中识别机械敏感和不敏感的膀胱和结直肠背根神经节神经元的“化学型”。我们假设，有显着差异的化学型之间的MIA和mechanosensitive传入，以及不同的mechanosensitive传入，进一步，器官之间。 公共卫生相关性：膀胱疼痛综合征和肠易激综合征是慢性的、使人虚弱的内脏疾病，在女性中更常见，其中疼痛和超敏反应是最令人不安的症状。众所周知，这些疾病很难控制。本研究的目的是确定器官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。

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. PUBLIC HEALTH RELEVANCE: Painful bladder syndrome and irritable bowel syndrome are chronic, debilitating visceral disorders, more common in women, in which pain and hypersensitivity are the most troubling symptoms. These disorders are notoriously difficult to manage. The objective of this research is to determine the mechanisms by which organ pain and hypersensitivity arises and is maintained as a necessary step in developing better informed and more successful management strategies.