Effect of neonatal and adult stress on pelvic pain disorders and comorbidity

新生儿和成人压力对盆腔疼痛疾病和合并症的影响

基本信息

批准号：
9467483
负责人：
Julie A Carlsten Christianson
金额：
$ 32.84万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-25 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9467483
关键词：
Adult Adverse event Affect Affinity Aftercare Animal Model Anxiety Attenuated Binding Bladder Bladder Control Bladder Dysfunction Brain region CRF receptor type 1 CRF receptor type 2 Cell Degranulation Cell Nucleus Childhood Chronic Prostatitis Comorbidity Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Diagnosis Disease Divorce Etiology Exposure to Facilities and Administrative Costs Feedback Female Future Genitourinary system Glucocorticoid Receptor Glucocorticoids Goals Growth Factor Homeostasis Hyperalgesia Hypersensitivity Hypothalamic structure Image Increased frequency of micturition Individual Inflammation Inflammation Mediators Injury Interstitial Cystitis Irritable Bowel Syndrome Long-Term Effects Measures Mediating Medical Care Costs Mental Depression Midbrain structure Mood Disorders Mus Neonatal Neonatal Intensive Care Units Nervous system structure Neurogenic Inflammation Neuronal Plasticity Neuropeptides Organ Output Pain Disorder Patients Pattern Pelvic Pain Peripheral Pontine structure Population Predisposition Prevalence Process Quality of life Recording of previous events Regulation Reporting Risk Factors Rodent Model Severities Sexual abuse Stress Structure Symptoms Syndrome Testing Trauma Urination Vagina Visceral Vulvodynia Water Woman abuse neglect adverse childhood events biological adaptation to stress central pain chronic pain chronic pelvic pain coping cost cytokine design early experience early life stress endometriosis experience experimental study gastrointestinal system hypothalamic-pituitary-adrenal axis insight mast cell maternal separation optimal treatments pain patient pain perception pain processing patient subsets peripheral pain physical abuse postnatal public health relevance receptor binding receptor expression response therapeutic target treatment strategy urocortin

项目摘要

DESCRIPTION (provided by applicant): An estimated 20% of the US population suffers from chronic pelvic pain, which encompasses a number of debilitating disorders including interstitial cystitis, irritable bowel syndrome, vulvodynia, chronic prostatitis and endometriosis, and costs more than $30 billion in direct medical and indirect costs annually. Up to 50% of women with chronic pelvic pain experience symptoms from more than one disorder, creating a greater negative impact on quality of life and complicating already less-than-optimal treatment strategies. Early life stress or trauma is a significant risk factor for developing functional pain disorders and is due, in part, to altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which regulates stress response and influences the perception of pain. Proper feedback within the hypothalamus, as well as regulatory input from higher limbic structures, influences the response to stress and subsequent return to homeostasis. Several key molecules are involved in this process, including corticotropin releasing factor (CRF), the principal initiator of the strss response through the CRF1 receptor; the related urocortins (Ucn), which can inhibit stress response through the CRF2 receptor; and glucocorticoids, which mediate downstream stress responses, as well as influence both positive and negative feedback onto the HPA axis. Rodent models of neonatal stress display disruption of proper feedback onto the HPA axis, resulting in visceral hyperalgesia, permanent changes in central and peripheral pain processing, and increased peripheral expression of inflammatory mediators. The goal of the current proposal is to understand how early life stress predisposes an individual to developing pelvic pain syndromes during adulthood. Our central hypothesis is that neonatal maternal separation (NMS) disrupts proper functioning of CRF-responsive brain regions and peripheral targets, resulting in altered bladder function and sensitivity, as well as enhanced susceptibility to stress-induced symptomology and comorbidity. We have designed three specific aims (SAs) to test this hypothesis. SA1 will determine the effect of neonatal and adult stress on limbic regulation of the HPA axis and downstream neurogenic inflammation of the bladder. SA2 will examine how neonatal and adult stress affects central and peripheral CRF/Ucn2-dependent control of micturition. SA3 will evaluate the efficacy of CRF antagonism for attenuating neonatal and adult stress-induced bladder dysfunction, hypersensitivity and neurogenic inflammation, as well as comorbid vaginal hypersensitivity. At the completion of this project, we will have gained new information about how early life stress drives neuronal plasticity, primes the nervous system for future insult, and increases the susceptibility for developing comorbid functional pain disorders. By focusing on stress-induced changes in visceral sensitivity, we will gain insight as to how best treat a specific subpopulation of patients suffering from IC, vulvodynia, and potentially a number of other comorbid stress-induced functional pain disorders.

描述（由申请人提供）：估计有 20% 的美国人口患有慢性盆腔疼痛，其中包括多种使人衰弱的疾病，包括间质性膀胱炎、肠易激综合征、外阴痛、慢性前列腺炎和子宫内膜异位症，并且花费超过 300 亿美元每年的直接医疗和间接费用。高达 50% 的慢性盆腔疼痛女性会出现不止一种疾病的症状，这对生活质量产生更大的负面影响，并使本已不太理想的治疗策略变得更加复杂。早期生活压力或创伤是发生功能性疼痛的重要危险因素疾病，部分原因是下丘脑-垂体-肾上腺（HPA）轴的功能改变，该轴调节应激反应并影响疼痛的感知。下丘脑内的适当反馈以及来自较高边缘结构的调节输入会影响对压力的反应以及随后恢复体内平衡。这一过程涉及几个关键分子，包括促肾上腺皮质激素释放因子 (CRF)，它是通过 CRF1 受体产生应激反应的主要引发剂；相关的尿皮质素（Ucn），可通过CRF2受体抑制应激反应；和糖皮质激素，介导下游应激反应，并影响 HPA 轴的正反馈和负反馈。新生儿应激的啮齿动物模型显示 HPA 轴的正确反馈受到破坏，导致内脏痛觉过敏、中枢和外周疼痛处理的永久性变化以及炎症介质的外周表达增加。当前提案的目标是了解早期生活压力如何使个体在成年期间容易患上盆腔疼痛综合征。我们的中心假设是，新生儿母体分离 (NMS) 会破坏 CRF 反应性大脑区域和外周目标的正常功能，导致膀胱功能和敏感性改变，以及对压力引起的症状和合并症的易感性增加。我们设计了三个具体目标（SA）来检验这一假设。 SA1 将确定新生儿和成人应激对 HPA 轴边缘调节和膀胱下游神经源性炎症的影响。 SA2 将研究新生儿和成人压力如何影响中枢和外周 CRF/Ucn2 依赖性排尿控制。 SA3将评估CRF拮抗剂对减轻新生儿和成人应激性膀胱功能障碍、过敏和神经源性炎症以及共病阴道过敏的功效。该项目完成后，我们将获得有关早期生活压力如何驱动神经元可塑性、如何为神经系统未来的损伤做好准备以及如何增加罹患共病功能性疼痛障碍的易感性的新信息。通过关注压力引起的内脏敏感性变化，我们将深入了解如何最好地治疗患有 IC、外阴痛和潜在的许多其他共病压力引起的功能性疼痛疾病的特定患者亚群。