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：
10374858
负责人：
Julie A Carlsten Christianson
金额：
$ 39.97万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10374858
关键词：
Acute Adult Affective Attenuated Automobile Driving Behavior Bladder Brain Brain-Derived Neurotrophic Factor Clinical DNA DNA Methylation Development Epigenetic Process Exercise Exhibits Exposure to Female Gene Expression Genes Genitourinary system Hippocampus (Brain)Hypersensitivity Impairment Lateral Life Magnetic Resonance Imaging Major Depressive Disorder Measures Mediating Methylation Modeling Modification Mood Disorders Moods Mus Neonatal Outcome Output Pain Pain Disorder Patients Pelvic Pain Phenotype Physical activity Population Populations at Risk Predisposition Process Prostate Recording of previous events Regulation Reporting Rewards Running Severities Signal Transduction Stress Symptoms Testing Therapeutic Intervention Trauma Urination Vagina Water acute stress allodynia biological adaptation to stress central pain chronic painful condition comorbidity early experience early life stress effective therapy gray matter hypothalamic-pituitary-adrenal axis in vivo inflammatory marker inhibitor male maternal separation mouse model negative mood neurochemistry neurogenesis neuroimaging novel pain perception pain processing prevent response sedentary sex spectroscopic imaging symptomatic improvement urologic chronic pelvic pain syndrome

项目摘要

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.

项目摘要慢性疼痛和情绪障碍是高度合并的，尤其是在早期病史的患者中压力（EL）或创伤。在泌尿科慢性骨盆疼痛综合征（UCPP）的患者中，EL的严重程度已经与集中式疼痛表型有关，患者报告了更大的疼痛和负面情绪和症状改善的可能性降低。神经影像学研究揭示了功能连通性的变化可能会特别易于使用ELS的UCPPS患者更大的症状负担和合并症。 ELS还与海马灰质体积减少和胁迫响应基因上的DNA甲基化增加，特别是在重度抑郁症患者中， UCPPS的常见合并症。海马对下丘脑 - 垂体 - 肾上腺负调节（HPA）轴，轴介导了压力反应，并且在集中式疼痛障碍患者中经常会改变。自愿运动是大多数情绪和集中疼痛障碍的有效治疗方法，并且显着增加海马神经发生，并已被证明会影响表观遗传修饰。我们的鼠标使用新生儿母体分离（NMS）的EL模型表明泌尿生殖力超敏反应，增加膀胱输出，广泛的异常性疾病，奖励行为受损以及海马改变的证据 HPA轴的调节。这些结果可能会因急性暴露于水应力而加剧（WAS）成年后，并被志愿轮跑衰减。在这里，我们提供了初步证据随后的海马灰质体积减少，DNA甲基化和钝化的神经化学信号是，表明降低的海马完整性可能会推动与NMS相关的结果，类似于在临床人群中观察到了什么。我们的中心假设是ELS诱导的变化海马可以通过增加体育锻炼来改变，从而衰减泌尿生殖器和广泛高敏性。我们将以两个具体的目的来检验这一假设。我们的第一个特定目标将决定是否增强体育锻炼可以防止海马的结构和神经化学变化 NMS小鼠急性应激暴露的敏感性。我们的第二个特定目标将决定DNA的影响海马在与NMS相关的结果上的甲基化以及该过程是否可以通过增加体育锻炼。该项目完成后，我们将获得新颖而重要的有关ELS对海马完整性的影响的信息，我们已将其确定为潜在的集成商集中式疼痛和合并情绪障碍。确定增加自愿体育锻炼的影响如何与EL相关的海马和敏感性变化将为使用运动作为一种进一步的证据强大的非药物治疗干预措施，用于治疗具有EL史的UCPPS患者可能会阻止处于危险人群中的症状发展。