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

项目摘要 慢性疼痛和情绪障碍高度并存，特别是在有早期生活史的患者中。 压力(ELS)或创伤。在尿路慢性盆腔疼痛综合征(UCPPS)患者中，ELS的严重性 与集中性疼痛表型有关，患者报告更广泛的疼痛和 消极情绪，降低症状改善的可能性。神经成像研究显示功能 连接性改变可能特别使患有ELS的UCPPS患者更容易出现症状负担 和合并症。ELS还与海马灰质体积的减少和 应激反应基因的DNA甲基化增加，特别是在患有严重抑郁障碍的患者中， UCPPS的一种常见共病。海马体负向调节下丘脑-垂体-肾上腺 (HPA)轴，它介导应激反应，在中枢性疼痛障碍患者中经常改变。 自愿锻炼是治疗大多数情绪和集中性疼痛障碍的有效方法，而且显著 增加海马神经发生，并已被证明影响表观遗传修饰。我们的老鼠 使用新生儿母体分离(NMS)的ELS模型显示泌尿生殖系统过敏，增加 膀胱排出量、广泛性痛觉异常、奖赏行为受损和海马区改变的证据 HPA轴的调节。这些结果可能会因急性暴露于避水压力而加剧。 (曾经)成年，通过自愿的车轮奔跑而变得虚弱。在这里，我们提供了初步证据 海马灰质体积减少、DNA甲基化和神经化学信号迟钝 是，表明海马体完整性降低可能是NMS相关结果的驱动因素，类似于 在临床人群中观察到的情况。我们的中心假设是ELS诱导的 海马体可以通过增加体力活动来改变，从而减弱泌尿生殖系统和 过敏症。我们将在两个具体目标上检验这一假设。我们的第一个具体目标将决定 增加体力活动可以防止海马体结构和神经化学变化 NMS小鼠对急性应激暴露的敏感性。我们的第二个具体目标将决定DNA的影响 海马区甲基化对NMS相关结果的影响以及这一过程是否可以被 增加体力活动。在这个项目完成后，我们将获得新的和重要的 ELS对海马区完整性的影响的信息，我们已经确定它是一个潜在的整合因子 集中的疼痛和共病的情绪障碍。确定自愿体力活动的增加如何影响 ELS相关的海马区和敏感性的变化将为运动作为一种 强有力的非药物治疗干预治疗有ELS和UCPPS病史的UCPPS患者 有可能防止高危人群出现症状。

Project Summary Chronic pain and mood disorders are highly comorbid, particularly in patients with a history of early life stress (ELS) or trauma. In patients with Urologic Chronic Pelvic Pain Syndromes (UCPPS), the severity of ELS has been associated with a centralized pain phenotype with patients reporting greater widespread pain and negative mood, and reduced likelihood of symptom improvement. Neuroimaging studies revealed functional connectivity changes that may specifically predispose UCPPS patients with ELS to greater symptom burden and comorbidity. ELS has also been correlated with reductions in hippocampal gray matter volume and increased DNA methylation on stress-responsive genes, particularly in patients with major depressive disorder, a common comorbidity of UCPPS. The hippocampus negatively regulates the hypothalamic-pituitary-adrenal (HPA) axis, which mediates the stress response and is often altered in patients with centralized pain disorders. Voluntary exercise is an effective treatment for most mood and centralized pain disorders and significantly increases hippocampal neurogenesis and has been shown to impact epigenetic modifications. Our mouse model of ELS using neonatal maternal separation (NMS) demonstrates urogenital hypersensitivity, increased bladder output, widespread allodynia, impaired reward behaviors, and evidence of altered hippocampal regulation of the HPA axis. These outcomes can be exacerbated by acute exposure to water avoidance stress (WAS) in adulthood and attenuated by voluntary wheel running. Here we provide preliminary evidence of reduced hippocampal gray matter volume, DNA methylation, and blunted neurochemical signals following WAS, suggesting that reduced hippocampal integrity may be driving the NMS-related outcomes, similar to what has been observed in clinical populations. Our central hypothesis is that ELS-induced changes in the hippocampus can be modified by increasing physical activity, thereby attenuating urogenital and widespread hypersensitivity. We will test this hypothesis in two specific aims. Our first specific aim will determine whether increasing physical activity can prevent structural and neurochemical changes in the hippocampus and susceptibility to acute stress exposure in NMS mice. Our second specific aim will determine the impact of DNA methylation in the hippocampus on NMS-related outcomes and whether this process can be attenuated by increasing physical activity. At the completion of this project we will have gained novel and important information on the impact of ELS on hippocampal integrity, which we have identified as a potential integrator of centralized pain and comorbid mood disorders. Determining how increasing voluntary physical activity impacts ELS-related hippocampal and sensitivity changes will provide further evidence for the use of exercise as a powerful non-pharmacologic therapeutic intervention for treating UCPPS patients with a history of ELS and possibly preventing the development of symptoms in at-risk populations.