Examination of mu opioid mediated pain vulnerability in combat mild Traumatic Brain Injury

美国每年有近200万人遭受创伤性脑损伤（TBI）和轻度TBI（mTBI） 被认为是参与伊拉克和阿富汗冲突的人的“标志性伤害”。受伤后的疼痛 发生在>50%的时间，干扰临床进程，干扰社区整合，并显着 增加了治疗费用。尽管疼痛被认为是一个重要的公共卫生问题， mTBI中疼痛的病理生理学目前是未知的，这限制了新的和有效的治疗方法的开发。 治疗。这项研究的长期目标是确定增加疼痛的生物标志物 创伤性脑损伤后的脆弱性，可用于改善慢性疼痛的预防和治疗， 我们的退伍军人。本修订申请的直接目标是检查阿片类药物的作用， 在战斗期间持续mTBI的退伍军人中增加疼痛脆弱性的传输和电路。 我们的中心假设是，脑Mu（μ）-阿片受体（莫尔）的可用性将显示区域差异， 有和没有慢性疼痛的mTBI退伍军人，在共病疼痛中观察到最大程度的减少 mTBI组。我们将使用新的混合正电子发射断层扫描和磁共振成像 （PET-MRI）平台，提供有关血流动力学的补充和同步信息 反应和神经递质激活，从而允许直接分类的功能，内源性 疼痛和mTBI患者的疼痛控制。这项工作将允许确定行为， 阿片能神经回路的微结构、功能和分子完整性及其与临床疼痛的关系 行为和生活质量。在强有力的初步数据的指导下，中心假设将通过以下方式进行检验： 追求两个具体目标：1）检查mTBI和慢性疼痛对患者的补充影响。 疼痛调节系统的完整性; 2）区分mTBI和慢性TBI的互补影响， 疼痛对疼痛调节系统的影响。这项工作意义重大，因为它将提供：1） mTBI后疼痛机制和增强的疼痛脆弱性;以及2）更好的成像工具来检测疼痛 mTBI后。退伍军人经常被开阿片类药物止痛。这些药物滥用的可能性很大， 内源性阿片系统的变化可能有助于改变这些药物的奖励作用; 因此，mTBI个体可能特别易受外源性阿片类药物的影响。目前的提案填补了 在理解莫尔如何介导神经传递（阿片类药物的主要靶点）方面存在重要差距 药物，在疼痛和mTBI的影响。 !

Nearly 2 million people in the United States sustain traumatic brain injury(TBI) every year and mild TBI(mTBI) is considered a “signature injury” of those involved in Iraq and Afghanistan conflicts. Pain after such injury occurs in >50% of the time, worsens clinical course, interferes with community integration, and dramatically increases the costs of treatment. Despite pain being considered an important public health issue, the pathophysiology of pain in mTBI is currently unknown, which limits development of novel and effective treatments. The long-term goal of this research is to determine biological markers for the increased pain vulnerability after traumatic brain injury that can be used to improve chronic pain prevention and treatments in our Veterans. The immediate goals of this revised application are to examine the role of opioidergic transmission and circuitry in the increased pain vulnerability in Veterans who sustained mTBI during combat. Our central hypothesis is that brain Mu (μ)-opioid receptor (MOR) availability will show regional variability in Veterans with combat mTBI with and without chronic pain, with most decrease observed in the co-morbid pain and mTBI group. We will use novel hybrid Positron Emission Tomography and Magnetic Resonance Imaging (PET-MRI) platform that provides complementary and simultaneous information about the hemodynamic response and neurotransmitter activation and thus allows direct classification of function of the endogenous pain control in individuals who has pain and mTBI. This work will allow determination of behavioral, microstructural, functional and molecular integrity of the opioidergic circuitry and its relationship to clinical pain behaviors and quality of life. Guided by strong preliminary data the central hypothesis will be tested by pursuing two specific aims: 1) To examine the complementary impact of mTBI and chronic pain on the integrity of pain modulatory systems; 2) To distinguish the complementary impact of mTBI and chronic pain on the capability of pain modulatory systems. This work is significant since it will provide: 1) a mechanism for pain and enhanced pain vulnerability following mTBI; and 2) better imaging tool to detect pain after mTBI. Veterans are often prescribed opioids for pain. These drugs have a high potential for abuse and changes in the endogenous opioid system may contribute to alterations in the rewarding effects of these drugs; thus mTBI individuals may be particularly vulnerable to exogenous opioids. The current proposal fills an important gap in understanding how MOR mediated neurotransmission, the primary target of opioid medications, is affected in pain and mTBI. !