Deciphering the hormonal and nociceptive mechanisms underlying bladder pain

描述（由申请人提供）：流行病学研究显示痛经与慢性盆腔疼痛（CPP）疾病（如膀胱疼痛综合征（PBS））之间存在高度共病性。使用口服避孕药（OCs）的激素抑制痛经被广泛用于治疗这些疾病，但结果不一;它们对盆腔伤害感受机制的影响仍不清楚。我们的长期目标是为CPP制定预防策略和有效的治疗方法。许多女性CPP状况似乎与重复性盆腔炎诱导的子宫炎症有关，并导致邻近盆腔器官的疼痛致敏或跨器官致敏（COS）。该建议的目的是确定膀胱COS的神经介导的伤害性、激素和心理机制。反过来，我们将探讨这些途径的基础上减少实验性膀胱疼痛后，管理的OC。从机制上讲，据信慢性疼痛涉及下行抑制的损伤，下行抑制是负责抑制脊髓疼痛受体的脑干通路。临床上，这种功能障碍伴随着疼痛敏感性的广泛变化。我们最近发现，中度至重度痛经的妇女表现出广泛的机械疼痛敏感性，以及膀胱敏感性的脆弱性。与现有CPP患者相比，痛经患者因较少受焦虑或抑郁的混杂而成为研究COS的理想对象。然而，在实验测试中，患有无症状膀胱疼痛（D+COS表型）的痛经患者也具有PBS的关键特征，即机械性阴道刺激后的长期疼痛，这表明他们具有发展慢性疼痛的高风险。我们的初步数据显示，OC的使用与膀胱疼痛较少，支持的想法，月经疼痛的激素抑制改善疼痛的COS的伤害性机制。因此，我们将通过两个目的来检验这一假设，即重复的月经疼痛发作会降低下行抑制并增加对COS的脆弱性，而连续的OC给药将逆转这种缺陷。目标一：确定痛经伴膀胱疼痛敏感的女性是否表现出与已建立的CPP一致的神经生理学特征。将有和没有COS和PBS患者的痛经患者与对照组进行实验性疼痛敏感性测试，测量下行抑制和骨盆和膀胱敏感性。目标二：通过一项周期性和连续性OC试验，区分循环性激素和重复致敏事件（疼痛的月经期）对膀胱疼痛下行和外周机制的个体作用。这种创新的方法探索了一种独特的临床前表型，具有一系列新颖的感官评估。这一建议是重要的，因为确定潜在的尿道介导的COS及其相对激素反应性的机制是至关重要的，以改善CPP治疗。制定一项减少膀胱疼痛早期体征的策略有可能预防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.