Mechanisms of Stress-Induced Pain in Veterans

多次伊拉克自由行动/持久自由行动/新黎明行动(OIF/OEF/OND) 退伍军人经历慢性疼痛，创伤后应激等并存疾病会加剧这种疼痛 精神障碍(PTSD)和抑郁。值得注意的是，提供有效治疗的临床需求尚未得到满足。 治疗慢性疼痛。开发新疗法的一个障碍是缺乏对 神经递质和大脑回路是慢性疼痛持续存在的原因。因此，这份职业 开发应用程序将提供必要的培训，以培养独立的退伍军人科学家 研究导致应激引起的慢性疼痛的新的大脑回路。 目的：这项研究的目的是确定导致持续应激的大脑回路。 使用包括光遗传技术在内的有针对性的大脑操作来诱导疼痛和共病行为。 最重要的假设是，应激导致边缘脑回路内的信号不平衡。 会产生持续性的疼痛过敏。 研究计划：该项目将利用两个相互关联、独立的具体目标。具体目标1将 应激诱导内侧皮质促肾上腺皮质激素释放因子信号增强的假说 前额叶皮质导致持续的内脏和躯体疼痛样行为。《特定目标2》将测试 假设边缘脑区之间的信号不平衡，受促肾上腺皮质激素释放的调节 因子和谷氨酸能受体与慢性应激诱导的超敏反应有关。我们将使用 靶向立体定向手术、插管植入、药物微量注射和激光的组合 刺激以改变清醒、自由活动的大鼠的伤害性、焦虑性和抑郁性行为。 培训计划：通过他的指导团队和顾问，应聘者将接受关于如何 进行研究计划所需的光遗传学、电生理学和行为学研究。 此外，候选人将参加正式课程，以促进其专业发展，包括 负责进行研究、统计分析和实验室管理。在正式的指导下 提高他的书面和口头交流，候选人将能够介绍这项研究的结果 在国内和国际会议上，并在高质量的期刊上发表研究结果。 预期结果：目标1中的研究将证明，压力诱导的 促肾上腺皮质激素释放因子在内侧前额叶皮质的表达导致内脏和 躯体敏感性，通过纹状体床核中的促肾上腺皮质激素释放因子受体发出信号 产生行为的终端虫。特定目标2将显示使用光遗传激活激活 终纹床核中杏仁核终末或内侧前额叶皮质终末的抑制 会使非应激大鼠产生内脏和躯体的过敏反应。这些实验还将证明 在刺激内侧前额叶皮质时抑制杏仁核信号(促肾上腺皮质激素释放因子) 慢性应激大鼠体内的信号(谷氨酸)将抑制疼痛行为。完成这些特定的 AIMS与拟议的指导和培训一起，将确保候选人发展他的研究 技能提交未来的退伍军人奖励金，并最终成为一名终身退伍军人研究职业科学家。 对退伍军人健康的意义：从科学上讲，这个项目的结果将确定一种新的 压力相关的大脑回路，以及调节慢性疼痛的特定神经递质。 识别慢性应激诱发疼痛的机制和回路可能导致新的靶点 用于治疗经历慢性疼痛的退伍军人，这是一个重大的未得到满足的医疗负担。 在专业方面，这个职业发展奖将产生一位具有以下能力的独立科学家 研究慢性疼痛的机制，为提高退伍军人的生活质量提供额外的工具。

Many Operation Iraqi Freedom/Operation Enduring Freedom/Operation New Dawn (OIF/OEF/OND) veterans experience chronic pain, which is worsened by co-morbid conditions such as post-traumatic stress disorder (PTSD) and depression. Significantly, there is an unmet clinical need to provide effective treatments for chronic pain. One hurdle for the development of new therapies is a lack of understanding which neurotransmitters and brain circuits are responsible for the persistence of chronic pain. Thus, this career development application will provide the necessary training to develop an independent VA scientist capable of researching novel brain circuitry responsible for the development of stress-induced chronic pain. OBJECTIVES: The objective of this study is to identify the brain circuitry responsible for persistent stress- induced pain and comorbid behaviors using targeted brain manipulations, including optogenetic techniques. The overarching hypothesis is that stress induces imbalanced signaling within the limbic brain circuitry to produce persistent pain hypersensitivity. RESEARCH PLAN: This project will utilize two interrelated, independent specific aims. Specific Aim 1 will test the hypothesis that stress-induced increases corticotropin-releasing factor signaling in the medial prefrontal cortex leads to persistent visceral and somatic pain-like behaviors. Specific Aim 2 will test the hypothesis that an imbalance in signaling between limbic brain regions, regulated by corticotropin-releasing factor and glutamatergic receptors, is responsible for chronic stress-induced hypersensitivity. We will use a combination of targeted stereotaxic surgeries, cannula implantations, drug microinfusions, and laser stimulation to modify nociceptive, anxiety-like, and depression-like behaviors in conscious, freely moving rats. TRAINING PLAN: Through his mentoring team and consultants, the candidate will receive training on how to conduct the optogenetic, electrophysiological, and behavioral studies needed to address the research plan. Additionally, the candidate will take formal courses to promote his professional development, including responsible conduct of research, statistical analysis, and laboratory management. With formal mentorship to improve his written and oral communication, the candidate will be able to present the findings of this research at national and international meetings and publish the results in quality journals. ANTICIPATED OUTCOMES: The research in Aim 1 will demonstrate that stress-induces increases in corticotropin-releasing factor expression within the medial prefrontal cortex leading to enhanced visceral and somatic sensitivity, which signals through corticotropin-releasing factor receptors in the bed nucleus of the stria terminalis to produce the behaviors. Specific Aim 2 will show using optogenetic activation that activation of amygdala terminals or inhibition of medial prefrontal cortex terminals in the bed nucleus of the stria terminalis will produce visceral and somatic hypersensitivity in non-stressed rats. The experiments will also demonstrate that inhibiting amygdala signaling (corticotropin-releasing factor) while stimulating medial prefrontal cortex signaling (glutamate) in chronically stressed rats will inhibit pain-like behaviors. Completion of these Specific Aims, along with the proposed mentoring and training, will ensure that the candidate develops his research skills to submit a future VA Merit grant and eventually becomes a life-long VA Research Career Scientist. SIGNIFICANCE TO VETERANS HEALTH: Scientifically, the results from this project will identify a novel stress-associated brain circuit, along with the specific neurotransmitters, that modulates chronic pain. Identification of the mechanisms and circuitry involved in chronic stress-induced pain could lead to new targets for therapies to treat veterans experiencing chronic pain, which is a significant unmet healthcare burden. Professionally, this career development award will produce an independent scientist with the capability of investigating chronic pain mechanisms to provide additional tools to improve the quality-of-life for veterans.