Deciphering the hormonal and nociceptive mechanisms underlying bladder pain

描述(申请人提供)：流行病学研究表明，痛经和慢性盆腔疼痛(CPP)疾病，如痛性膀胱综合征(PBS)之间有很高的共患率。使用口服避孕药(OCS)激素抑制痛经被广泛用于治疗这些疾病，但结果参差不齐；它们对涉及骨盆伤害性反应的机制的影响尚不清楚。我们的长期目标是开发CPP的预防策略和有效的治疗方法。许多女性CPP的情况似乎与重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感化，或跨器官敏感化(COS)。这项建议的目的是确定月经介导的伤害性、荷尔蒙和心理机制对膀胱COS负责。反过来，我们将探索这些途径中的哪一条是在给药OCS后减少实验性膀胱疼痛的基础。从机制上讲，人们认为慢性疼痛涉及下行抑制的损害，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度的广泛变化。我们最近发现，中到重度痛经的女性表现出广泛的机械性疼痛敏感性，以及对膀胱敏化的易感性。与现有的CPP患者相比，痛经患者较少受到焦虑或抑郁的困扰，因此是研究COS的理想对象。然而，在实验测试中有无症状膀胱疼痛的痛经患者(D+COS表型)也有PBS的一个关键特征，即机械阴道刺激后持续疼痛，这表明他们发展为慢性疼痛的风险很高。我们的初步数据显示，OC的使用与较少的膀胱疼痛有关，支持荷尔蒙抑制月经疼痛改善COS潜在的伤害性机制的观点。因此，我们将检验这样一种假设，即反复发作月经疼痛会减少下行抑制并增加对COS的易感性，而持续服用OC将通过两个目的逆转这一缺陷。目的#1：确定痛经和伴随膀胱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。患有和不患有COS和PBS患者的痛经患者将在实验疼痛敏感性测试中与对照组进行比较，该测试测量下行抑制以及盆腔和膀胱的敏感性。目的#2：通过一项周期性和持续性OCS试验，区分循环性激素和反复致敏事件(痛经)在膀胱痛下行和外周机制中的个体作用。这种创新的方法探索了一种独特的临床前表型和一系列新颖的感官评估。这一建议意义重大，因为确定月经介导的COS的潜在机制及其相对激素反应性对于改善CPP的治疗至关重要。开发一种策略来减少膀胱疼痛的早期迹象有可能预防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.