Deciphering the hormonal and nociceptive mechanisms underlying bladder pain

破译膀胱疼痛背后的荷尔蒙和伤害性机制

• 批准号: 9036385
• 负责人: Frank Fu-sheng Tu
• 金额: $ 47.74万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9036385
• 关键词: Abdomen; Address; Affect; Age; American; Animals; Anxiety; Benign; Bladder; Bladder Control; Brain Stem; Chronic; Comorbidity; Conflict (Psychology); Contraceptive Usage; Data; Dysmenorrhea; Endometrial; Epidemiologic Studies; Etiology; Evaluation; Event; Exhibits; Female; Functional disorder; Goals; Gonadal Steroid Hormones; Health; Hemorrhage; Hormonal; Hormones; Human; Hyperalgesia; Impairment; Individual; Infection; Inflammation; Injury; Interstitial Cystitis; Irritable Bowel Syndrome; Link; Measures; Mechanics; Mediating; Menstrual cycle; Menstruation; Mental Depression; Migraine; Mission; Nerve; Neurogenic Inflammation; Neurons; Nociception; Oral Contraceptives; Organ; Pain; Pain Disorder; Pain Threshold; Pain management; Pathway interactions; Patient Self-Report; Patients; Pelvic Pain; Pelvis; Peripheral; Phenotype; Prevention strategy; Process; Psychological Factors; Public Health; Reporting; Risk; Risk Marker; Sensory; Spinal; Spine pain; Stimulus; Temporomandibular Joint; Testing; Therapeutic; Urologic Diseases; Vagina; Visceral; Withdrawal; Woman; Work; bladder pain; chronic pain; chronic pelvic pain; clinical phenotype; cytokine; effective therapy; high risk; improved; innovation; neurophysiology; novel; pain receptor; pre-clinical; prevent; prospective; psychologic; randomized trial; reproductive; reproductive hormone; response; treatment strategy; urologic

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.

描述（由申请人提供）：流行病学研究表明痛经和慢性盆腔疼痛（CPP）疾病（例如膀胱疼痛综合征（PBS））之间存在高度共病。使用口服避孕药 (OC) 抑制痛经的激素被广泛用于治疗这些疾病，但效果参差不齐；它们对骨盆伤害感受机制的影响仍不清楚。我们的长期目标是制定 CPP 的预防策略和有效的治疗方法。许多女性 CPP 病症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或跨器官敏感 (COS)。该提案的目的是确定导致膀胱 COS 的月经介导的伤害性、激素和心理机制。反过来，我们将探索这些途径中的哪一条是口服口服避孕药后实验性膀胱疼痛减轻的基础。从机制上讲，人们认为慢性疼痛与下行抑制受损有关，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，患有中度至重度痛经的女性表现出广泛的机械性疼痛敏感性，并且容易对膀胱过敏。与现有的 CPP 患者相比，痛经患者更适合研究 COS，因为其较少受到焦虑或抑郁的干扰。然而，实验测试中出现无症状膀胱痛（D+COS 表型）的痛经患者也具有 PBS 的一个关键特征，即机械性阴道刺激后的长期疼痛，这表明他们存在发生慢性疼痛的高风险。我们的初步数据显示，使用 OC 与减少膀胱疼痛有关，这支持了荷尔蒙抑制经痛可改善 COS 背后的伤害性机制的观点。因此，我们将检验以下假设：经期疼痛的反复发作会减少下行抑制并增加对 COS 的脆弱性，而持续使用 OC 会通过两个目标扭转这种缺陷。目标#1：确定患有痛经并伴有膀胱疼痛敏感性的女性是否表现出与已建立的 CPP 一致的神经生理学特征。患有或不患有 COS 和 PBS 的痛经患者将在实验性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骨盆和膀胱敏感性。目标#2：通过循环和连续 OC 试验，区分循环性激素和重复敏化事件（疼痛经期）对膀胱疼痛下行和外周机制的个体贡献。这种创新方法通过一系列新颖的感官评估探索了独特的临床前表型。这一提议意义重大，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 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。