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

• 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
• 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

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共病的，特别是在有早期生活史的患者中 压力（ELS）或创伤。在泌尿系慢性盆腔疼痛综合征（UCPPS）患者中，ELS的严重程度 与集中性疼痛表型相关，患者报告更广泛的疼痛， 负面情绪，以及症状改善的可能性降低。神经影像学研究显示 连接性变化可能使患有ELS的UCPPS患者特别容易出现更大的症状负担 和科摩罗。ELS也与海马灰质体积的减少相关， 应激反应基因的DNA甲基化增加，特别是在重度抑郁症患者中， UCPPS的一种常见合并症。海马负调节下丘脑-垂体-肾上腺 (HPA)轴，这介导的压力反应，往往是改变患者与集中性疼痛障碍。 自愿运动是一种有效的治疗大多数情绪和集中性疼痛障碍， 增加海马神经发生，并已显示影响表观遗传修饰。我们的小鼠 使用新生儿母体分离（NMS）的ELS模型显示泌尿生殖系统超敏反应，增加 膀胱输出，广泛异常性疼痛，奖励行为受损，以及海马神经元改变的证据。 HPA轴的调节。这些结果可能会加剧急性暴露于水回避压力 (WAS)在成年期，并通过自愿的车轮运行衰减。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减弱， WAS，表明海马完整性降低可能是导致NMS相关结局的原因，类似于 在临床人群中观察到的情况。我们的中心假设是，ELS引起的变化， 海马可以通过增加体力活动来改变，从而减少泌尿生殖系统和广泛的 超敏反应我们将在两个具体目标中检验这一假设。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的结构和神经化学变化， NMS小鼠对急性应激暴露的易感性。我们的第二个具体目标将决定DNA的影响 海马甲基化对NMS相关结果的影响，以及是否可以通过 增加身体活动。在这个项目完成后，我们将获得新的和重要的 关于ELS对海马完整性的影响的信息，我们已经确定它是一种潜在的整合剂， 集中性疼痛和共病情绪障碍。确定增加自愿身体活动如何影响 ELS相关的海马和敏感性变化将为运动作为一种治疗方法提供进一步的证据。 用于治疗有ELS病史的UCPPS患者的强效非药物治疗干预， 可能防止高危人群出现症状。