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：
9267976
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 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9267976
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 Event 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 Life Stress Long-Term Effects Measures Mediating Medical Mental Depression Midbrain structure Mood Disorders Mus Neonatal Neonatal Intensive Care Units Nervous system structure Neurogenic Inflammation Neuronal Plasticity Neuropeptides Organ Output Pain Pain Disorder Patients Pattern Pelvic Pain Perception 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 biological adaptation to stress central pain chronic pain chronic pelvic pain coping cost cytokine design early experience endometriosis experience experimental study gastrointestinal system hypothalamic-pituitary-adrenal axis insight mast cell maternal separation 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％的美国人群患有慢性骨盆疼痛，其中包括许多令人衰弱的疾病，包括间质膀胱炎，肠易激综合征，外阴痛，慢性预性炎和子宫内膜异位症以及直接医疗和独立成本超过300亿美元。多达50％的患有慢性骨盆疼痛的妇女会出现多种疾病的症状，对生活质量产生更大的负面影响，并使已经比较理想的治疗策略复杂化。早期生活压力或创伤是发展功能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，该轴调节压力反应并影响疼痛的感知。下丘脑内的适当反馈以及高度边缘结构的调节输入会影响压力的反应，并随后恢复对体内平衡的反应。该过程涉及几个关键分子，包括皮质激素释放因子（CRF），这是通过CRF1受体的STRS响应的主要引发剂；相关的泌尿皮质素（UCN），可以通过CRF2受体抑制应激反应；和糖皮质激素，介导下游应力反应，并影响HPA轴的正反馈和负反馈。新生儿应力的啮齿动物模型显示出适当的反馈在HPA轴上的破坏，导致内脏痛觉过敏，中央疼痛处理和外周疼痛处理的永久变化以及炎症介体的外围表达增加。当前提议的目的是了解早期生活压力如何使个人在成年期间患上骨盆疼痛综合征。我们的中心假设是，新生儿母体分离（NMS）破坏了CRF反应性大脑区域和外围靶标的适当功能，从而导致膀胱功能和灵敏度的改变，并增强对压力诱导的症状和合并症的易感性。我们设计了三个特定目标（SAS）来检验这一假设。 SA1将确定新生儿和成人应力对HPA轴边缘调节的影响以及膀胱的下游神经源性炎症。 SA2将研究新生儿和成人压力如何影响排尿中的中央和外围CRF/UCN2依赖性控制。 SA3将评估CRF拮抗作用的疗效，以减轻新生儿和成人应激引起的膀胱功能障碍，超敏反应和神经发生炎症以及阴道性高敏性。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的新信息，神经系统以使未来的侮辱以及增加患有合并功能性疼痛障碍的敏感性。通过专注于应激引起的内脏敏感性变化，我们将了解如何最好地治疗患有IC，外阴痛的患者的特定亚群，以及可能其他合并症的胁迫诱发的功能性疼痛障碍。