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

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，包括许多使人衰弱的疾病，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，每年的直接医疗和间接费用超过300亿美元。高达50%的慢性盆腔疼痛女性会经历一种以上疾病的症状，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复杂。早期生活压力或创伤是发展功能性疼痛的重要危险因素 疼痛是一种神经系统疾病，部分是由于下丘脑-垂体-肾上腺（HPA）轴功能的改变，HPA轴调节应激反应并影响疼痛感知。下丘脑内的适当反馈，以及来自高级边缘系统结构的调节输入，影响对压力的反应和随后的稳态恢复。几个关键分子参与这一过程，包括促肾上腺皮质激素释放因子（CRF），通过CRF 1受体的应激反应的主要引发剂;相关的尿皮质素（Ucn），可以通过CRF 2受体抑制应激反应;和糖皮质激素，介导下游应激反应，以及影响HPA轴的正反馈和负反馈。新生儿应激的啮齿动物模型显示对HPA轴的适当反馈的破坏，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。目前建议的目标是了解早期生活压力如何使个体在成年期患上盆腔疼痛综合征。我们的中心假设是，新生儿母亲分离（NMS）破坏CRF反应性脑区和外周靶点的正常功能，导致膀胱功能和敏感性改变，以及对应激诱导的膀胱病变和合并症的易感性增强。我们设计了三个具体的目标（SA）来验证这一假设。SA 1将确定新生儿和成人应激对HPA轴的边缘调节和膀胱的下游神经源性炎症的影响。SA 2将研究新生儿和成人应激如何影响中枢和外周CRF/Ucn 2依赖性排尿控制。SA 3将评价CRF拮抗作用减轻新生儿和成人应激诱导的膀胱功能障碍、超敏反应和神经源性炎症以及共病阴道超敏反应的疗效。在这个项目完成后，我们将获得关于早期生活压力如何驱动神经元可塑性的新信息，为未来的损伤做好神经系统的准备，并增加患共病功能性疼痛障碍的易感性。通过关注应激诱导的内脏敏感性变化，我们将深入了解如何最好地治疗患有IC、外阴痛和可能的其他一些共病应激诱导的功能性疼痛疾病的特定亚群患者。

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.