Cross Organ Mechanisms in Chronic Pelvic Pain

慢性盆腔疼痛的跨器官机制

• 批准号: 10656603
• 负责人: Frank Fu-sheng Tu
• 金额: $ 72.35万
• 依托单位: NORTHSHORE UNIVERSITY HEALTHSYSTEM
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656603
• 关键词: Acceleration; Accounting; Acute; Address; Afferent Neurons; Animals; Anti-Inflammatory Agents; Biological; Biological Assay; Bladder; Blood; Brain; Chronic; Clinical; Collection; Communication; Data; Development; Distress; Dysmenorrhea; Early Intervention; Electroencephalography; Equipment and supply inventories; Event; Event-Related Potentials; Exhibits; Follow-Up Studies; Functional disorder; Health; Home; Hypersensitivity; Impairment; Inflammation; Inflammatory; Inflammatory Response; Interstitial Cystitis; Irritable Bowel Syndrome; Knowledge; Leukocytes; Longitudinal Studies; Longitudinal, observational study; Measurement; Measures; Mediating; Methods; Mission; Natural History; Neurobiology; Neurologic; Non-Visceral; Organ; Outcome; Pain; Pain Disorder; Pain Free; Participant; Pathway interactions; Patients; Pelvic Pain; Pelvis; Perception; Persons; Phenotype; Pilot Projects; Populations at Risk; Prevention; Prevention strategy; Prospective Studies; Psychophysics; Quality of life; Questionnaires; Recording of previous events; Risk; Sampling; Sensory; Severities; Spinal; Symptoms; System; TLR4 gene; Testing; Time; United States National Institutes of Health; Vertebral column; Visceral; Whole Blood; Woman; aged; bladder pain; care costs; chronic pain; chronic pain patient; chronic painful condition; chronic pelvic pain; cohort; cost; density; effective therapy; endometriosis; experience; follow-up; health assessment; high risk; innovation; mindfulness meditation; multimodality; neural; neuromechanism; pain chronification; pain outcome; pain sensitivity; pain symptom; predicting response; prevent; productivity loss; prospective; psychologic; public health priorities; reproductive; response; screening; symptomatology; systemic inflammatory response; two-dimensional; virtual; young woman

Chronic pelvic pain (CPP) disorders cause significant distress and often lack effective treatments. Although dysmenorrhea is closely associated with 80% of cases of CPP, little is known about why only some women with menstrual pain go on to develop conditions like interstitial cystitis/bladder pain syndrome, irritable bowel syndrome, or endometriosis. Intriguingly, 20% of dysmenorrhea sufferers (without chronic pain) display a key feature of many CPP states, bladder hypersensitivity on noninvasive bladder filling, and appear on pilot studies at higher risk of CPP in one year. In this team’s prior studies, women with the dysmenorrhea with bladder pain phenotype (DYSB) also exhibit greater somatic symptom burden, experimental pain hypersensitivity, and psychological dysregulation—features found in many chronic pain patients. As little is known about the acute to CPP transition, this renewal application seeks to track pelvic pain symptomatology prospectively in DYSB women and to expand those initial mechanistic studies. Aim 1 is a two-year longitudinal study of 1050 young women oversampled for dysmenorrhea to find 150 DYSB cases and establish their risk trajectory for CPP symptoms vs. those with only dysmenorrhea (DYS only = 750) and healthy controls (HC = 150). Along with a virtual bladder filling screening test, other patient health factors potentially predicting development of CPP will be captured, including overall pelvic experiences and general sensory sensitivity. Aim 2 will investigate 100 DYSB and 100 controls (DYS only and HC) on two dimensions of CPP mechanistically—bladder hypersensitivity and multimodal hypersensitivity (a composite of experimentally evoked responses to nonvisceral quantitative sensory tests [QST]). Electroencephalography-based studies will further investigate which neurological mechanisms (i.e. ascending neural hyperexcitability, descending inhibition, and neural oscillations) underlie these two components and predict one-year worsening of CPP symptoms. Aim 3 studies whether another key mechanism of pain sensitization, Toll-like Receptor-4 inflammatory reactivity, influences CPP progression, using an integrated whole-blood collection and leukocyte culture system. This renewal application significantly extends this discovery of an at-risk phenotype by providing a method for expanding screening and characterizing reversible mechanisms. This essential followup study utilizes innovative combinations of QST with EEG measurements of brain activity to identify the mechanisms responsible for CPP-related-sensory abnormalities, alongside measures of systemic inflammatory reactivity that are strongly implicated in sensory hypersensitivity. Notably, if these are confirmed, candidate early interventions already exist to modulate these mechanisms, including mindfulness meditation and consistent anti-inflammatory use for dysmenorrhea. Successful completion of these studies would accelerate efforts to prevent the transition from acute to chronic pelvic pain, a major public health priority.

慢性盆腔疼痛（CPP）疾病会导致严重的痛苦，通常缺乏有效的治疗。虽然 痛经与80%的CPP病例密切相关，但很少有人知道为什么只有一些女性 月经疼痛会发展成间质性膀胱炎/膀胱疼痛综合征，肠易激综合征， 子宫内膜异位症有趣的是，20%的痛经患者（没有慢性疼痛）显示出一个关键点， 许多CPP状态的特征，非侵入性膀胱充盈的膀胱超敏反应，并出现在初步研究中 在一年内患CPP的风险更高。在这个团队先前的研究中，患有痛经伴膀胱疼痛的女性 表型（DYSB）也表现出更大的躯体症状负担，实验性疼痛超敏反应， 心理失调-在许多慢性疼痛患者中发现的特征。由于对急性 CPP过渡，本次更新申请旨在前瞻性跟踪DYSB中的盆腔疼痛病理学 并扩大这些初步的机械研究。目的1是一项为期两年的纵向研究， 对女性进行痛经过度抽样，发现150例DYSB病例并确定其CPP风险轨迹 症状与仅有痛经的患者（仅DYS = 750）和健康对照组（HC = 150）。沿着着 虚拟膀胱充盈筛选试验，其他可能预测CPP发生的患者健康因素将 包括整体骨盆体验和一般感官敏感度。目标2将调查100 DYSB和100个对照（仅DYS和HC）在CPP机械膀胱的两个维度上 超敏反应和多模式超敏反应（实验诱发的对 非内脏定量感觉测试[QST]）。基于脑电图的研究将进一步调查 哪些神经机制（即上行神经过度兴奋、下行抑制和神经过度兴奋） 振荡）是这两个组成部分的基础，并预测CPP症状的一年恶化。Aim 3研究 疼痛致敏的另一个关键机制，Toll样受体-4炎症反应性，是否影响 CPP进展，使用整合的全血采集和白细胞培养系统。此续订 本申请通过提供一种方法， 扩大筛选和表征可逆机制。这项重要的后续研究利用了 QST与脑电活动测量的创新组合，以确定机制 负责CPP相关的感觉异常，同时测量全身炎症 这些反应强烈地牵涉到感觉超敏性。值得注意的是，如果这些得到证实， 候选的早期干预措施已经存在，以调节这些机制，包括正念冥想 和一致的消炎用于痛经。成功完成这些研究将 加快努力，防止从急性骨盆疼痛转变为慢性骨盆疼痛，这是一个主要的公共卫生优先事项。

项目成果

Identification of experimental bladder sensitivity among dysmenorrhea sufferers.

• DOI: 10.1016/j.ajog.2018.04.030
• 发表时间: 2018-07
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: Hellman KM;Datta A;Steiner ND;Kane Morlock JN;Garrison EF;Clauw DJ;Tu FF
• 通讯作者: Tu FF

Somatic symptoms in women with dysmenorrhea and noncyclic pelvic pain.

患有痛经和非周期性盆腔疼痛的女性的躯体症状。

• DOI: 10.1007/s00737-018-0823-4
• 发表时间: 2018-10
• 期刊: Archives of women's mental health
• 作者: Zuckerman RM;Silton RL;Tu FF;Eng JS;Hellman KM
• 通讯作者: Hellman KM

Cortical Mechanisms of Visual Hypersensitivity in Women at Risk for Chronic Pelvic Pain.

有慢性盆腔疼痛风险的女性视觉过敏的皮质机制。

• DOI: 10.1101/2020.12.03.20242032
• 发表时间: 2021
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Kmiecik,MatthewJ;Tu,FrankF;Silton,RebeccaL;Dillane,KatlynE;Roth,GenevieveE;Harte,StevenE;Hellman,KevinM
• 通讯作者: Hellman,KevinM

Clinical profile of comorbid dysmenorrhea and bladder sensitivity: a cross-sectional analysis.

共病痛经和膀胱敏感性的临床特征：横断面分析。

• DOI: 10.1016/j.ajog.2019.12.010
• 发表时间: 2020
• 期刊: American journal of obstetrics and gynecology
• 影响因子: 9.8
• 作者: Tu,FrankF;Datta,Avisek;Atashroo,Diana;Senapati,Sangeeta;Roth,Genevieve;Clauw,DanielJ;Hellman,KevinM
• 通讯作者: Hellman,KevinM

Generalized sensory sensitivity is associated with comorbid pain symptoms: a replication study in women with dysmenorrhea.

全身感觉敏感性与共病疼痛症状相关：一项针对痛经女性的重复研究。

• DOI: 10.1097/j.pain.0000000000002676
• 发表时间: 2023
• 期刊: Pain
• 影响因子: 7.4
• 作者: Schrepf,Andrew;Hellman,KevinM;Bohnert,AmyM;Williams,DavidA;Tu,FrankF
• 通讯作者: Tu,FrankF