Deciphering the hormonal and nociceptive mechanisms underlying bladder pain

描述（由申请人提供）：流行病学研究表明痛经与慢性盆腔疼痛（CPP）疾病如膀胱疼痛综合征（PBS）之间有很高的合并症。使用口服避孕药（OCs）抑制痛经的激素被广泛用于治疗痛经，但效果不一；它们对盆腔痛觉相关机制的影响尚不清楚。我们的长期目标是制定预防策略和有效的治疗CPP。许多女性CPP病症似乎与反复月经引起的子宫炎症有关，并导致邻近盆腔器官的疼痛敏化，或跨器官敏化（COS）。本提案的目的是确定月经介导的痛觉，激素和心理机制负责膀胱COS。反过来，我们将探索这些途径中的哪一个是在给药后实验性膀胱疼痛减少的基础。从机制上讲，人们认为慢性疼痛涉及下行抑制的损伤，脑干通路负责抑制脊髓疼痛受体。临床上，这种功能障碍伴随着疼痛敏感性的广泛改变。我们最近发现，患有中度至重度痛经的女性表现出广泛的机械疼痛敏感性，以及对膀胱敏感的脆弱性。与现有的CPP患者相比，痛经患者较少受焦虑或抑郁的干扰，是研究COS的理想选择。然而，经实验检测，无症状膀胱疼痛（D+COS表型）的痛经患者也具有PBS的一个关键特征，即阴道机械刺激后疼痛持续，这表明他们有发展为慢性疼痛的高风险。我们的初步数据显示，口服避孕药与膀胱疼痛减轻有关，这支持了激素抑制月经疼痛可改善COS潜在伤害机制的观点。因此，我们将验证反复发作的月经疼痛会降低下行抑制并增加对COS的易感性的假设，而持续的口服避孕药会通过两个目的逆转这种缺陷。目的1：确定痛经合并膀胱疼痛敏感性的女性是否表现出与已建立的CPP一致的神经生理特征。伴有和不伴有COS的痛经患者以及PBS患者将与对照组进行疼痛敏感性实验测试，该测试测量下降抑制以及骨盆和膀胱敏感性。目的2：通过周期性和持续性膀胱疼痛的试验，区分循环性激素和反复致敏事件（痛经）对膀胱疼痛的下行和外周机制的个体贡献。这种创新的方法探索了一种独特的临床前表型与一系列新颖的感官评估。这一建议具有重要意义，因为确定月经介导的COS及其相对激素反应的机制对改善CPP治疗至关重要。制定减少膀胱疼痛早期症状的策略有可能预防CPP。

DESCRIPTION (provided by applicant): Epidemiological studies show high comorbidity between dysmenorrhea and chronic pelvic pain (CPP) disorders such as painful bladder syndrome (PBS). Hormonal suppression of dysmenorrhea using oral contraceptives (OCs) is widely used to treat these conditions, but with variable results; their influence on the mechanisms involved in pelvic nociception remains unclear. Our long-term goal is to develop prevention strategies and effective treatments for CPP. Many female CPP conditions appear linked to repetitive menstrual-induced uterine inflammation and result in pain sensitization of adjacent pelvic organs, or cross organ sensitization (COS). The objective of this proposal is to identify the menstrually-mediated nociceptive, hormonal and psychological mechanisms responsible for COS of the bladder. In turn, we will explore which of these pathways underlie a reduction in experimental bladder pain following administration of OCs. Mechanistically, it is believed chronic pain involves impairments in descending inhibition, the brainstem pathway responsible for inhibiting spinal pain receptors. Clinically, this dysfunction is accompanied by widespread changes in pain sensitivity. We recently identified that women with moderate to severe dysmenorrhea exhibit widespread mechanical pain sensitivity and as well as vulnerability to bladder sensitization. In contrast with existing CPP patients, dysmenorrhea patients are ideal to study COS because of less confounding by anxiety or depression. However, dysmenorrhea patients with silent bladder pain (the D+COS phenotype) on experimental testing also have a key feature of PBS, prolonged pain following mechanical vaginal provocation, suggesting they harbor a high risk of developing chronic pain. Our preliminary data show OC usage is associated with less bladder pain, supporting the idea that hormonal suppression of menstrual pain improves nociceptive mechanisms underlying COS. Therefore, we will test the hypothesis that repeated episodes of menstrual pain reduce descending inhibition and increase vulnerability to COS, while continuous OC administration will reverse this deficit, through two aims. Aim #1: To determine if women with dysmenorrhea and concomitant bladder pain sensitivity exhibit neurophysiological features consistent with established CPP. Dysmenorrhea sufferers with and without COS and PBS patients will be compared with controls on experimental pain sensitivity tests, which measure descending inhibition and pelvic and bladder sensitivity. Aim #2: To differentiate the individual contributions of circulating sex hormones and repeated sensitizing events (painful menstrual periods) on descending and peripheral mechanisms of bladder pain with a trial of cyclic and continuous OCs. This innovative approach explores a unique pre-clinical phenotype with a battery of novel sensory assessments. This proposal is significant because determining the mechanisms underlying menstrual-mediated COS and their relative hormonal responsiveness is critical to improve CPP treatment. Developing a strategy to reduce early signs of bladder pain has the potential to prevent CPP.