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: 9456112
• 负责人: Frank Fu-sheng Tu
• 金额: $ 7.83万
• 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/9456112
• 关键词: Abdomen; Address; Affect; Age; American; Animals; Anxiety; Benign; Bladder; Bladder Control; Brain Stem; Chronic; Clinical; Comorbidity; Conflict (Psychology); Contraceptive Usage; Data; Dysmenorrhea; Endometrial; Etiology; Evaluation; Event; Exhibits; Female; Functional disorder; Goals; Gonadal Steroid Hormones; 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; National Institute of Diabetes and Digestive and Kidney Diseases; Nerve; Neurogenic Inflammation; Neurons; Nociception; Oral Administration; Oral Contraceptives; Organ; Pain; Pain Disorder; Pain Threshold; Pain management; Pathway interactions; Patient Self-Report; Patients; Pelvic Pain; Pelvis; Periodicity; Peripheral; Phenotype; Prevention strategy; 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; epidemiology study; high risk; improved; innovation; neurophysiology; novel; pain receptor; pre-clinical; prevent; prospective; psychologic; public health relevance; 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，痛经和慢性骨盆疼痛（CPP）疾病（例如疼痛膀胱综合征（PBS））之间的合并症很高。使用口服避孕药（OC）广泛用于治疗这些疾病，但结果可变；它们对骨盆伤害感受的机制的影响尚不清楚。我们的长期目标是为CPP制定预防策略和有效治疗方法。许多女性CPP条件似乎与重复的月经引起的子宫炎症有关，并导致相邻的骨盆器官或跨器官敏化（COS）疼痛敏感。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，我们将探索执行OCS后实验性膀胱疼痛的减少是这些途径的基础。从机械上讲，据信慢性疼痛涉及降低抑制作用的损害，脑干途径负责抑制脊柱疼痛受体。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具有广泛的机械疼痛敏感性以及膀胱敏化的脆弱性。与现有的CPP患者相反，痛经性患者是研究COS的理想选择，因为焦虑或抑郁症的混淆较少。然而，实验测试中静音膀胱疼痛（D+COS表型）的痛经患者也具有PBS的关键特征，在机械阴道挑衅后长时间疼痛，表明它们具有慢性疼痛的高风险。我们的初步数据表明，OC的使用与膀胱疼痛减轻有关，支持了激素抑制月经疼痛的想法，可以改善COS依据的伤害性机制。因此，我们将测试以下假设，即重复的月经疼痛发作会减少降低的抑制和增加对COS的降低，而通过持续的OC进行了持续的危害，可以通过持续的perversiondersive cassection verseversive verseversive verseversivesiquiquics sivesiquss，这是我们的持续降低的目标。目标＃1：确定患有痛经和伴随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。患有或没有COS和PBS患者的痛经患者将与实验性疼痛敏感性测试的对照组进行比较，这些对照测量抑制作用以及骨盆和膀胱敏感性。目标＃2：通过对膀胱疼痛的下降和周围机制，通过对环状和连续OCS的试验来区分循环性激素的个体贡献和反复的敏感事件（痛苦的月经期）。这种创新的方法探索了具有一系列新型感觉评估的独特临床前表型。该提议很重要，因为确定月经介导的COS的基本机制，其相对激素反应性对于改善CPP治疗至关重要。制定一种减少早期膀胱疼痛迹象的策略有可能预防CPP。