Targeting Melanocortin-4 Receptors to Reduce Pain in U.S. Veterans

美国退伍军人更常被诊断为创伤后应激障碍(PTSD)和酒精 与普通人群相比，使用障碍(AUD)，患有创伤后应激障碍的个人经常在 使健康状况恶化的金额(如疼痛)，在美国造成巨大的健康和财政负担 各州。疼痛与创伤后应激障碍和AUD高度并存，但治疗策略不足以治疗个体 生活在两种或两种以上的诊断中，这些疾病背后的神经生物学机制是 定义不明确。这里提出的工作的最终目标是通过以下方式改善退伍军人的健康和生活质量 指导治疗策略，减轻创伤后应激障碍和/或AUD患者的疼痛。 该项目属于V.A.研究和开发生物医学实验室办公室的范围 研究与开发(BLR&D)服务目标，资助临床前生物医学和行为研究 疾病对退伍军人的健康很重要。更具体地说，这一创新的和临床相关的应用 提出将研究个体疼痛敏感性增加的神经生物学机制的工作。 忍受过创伤应激或依赖酒精的人。这项工作显然有潜力导致 退伍军人医疗保健工作取得重大进展。此应用程序建议使用啮齿动物模型来 研究脑黑素皮质素-4受体(MC4R)信号在痛觉过敏/痛觉异常中的作用 有酒精依赖或有精神创伤。我们将使用行为药理学技术 测试鼻腔给药的MC4R拮抗剂的治疗潜力，以减轻疼痛，与 全身性吗啡(临床黄金标准)。我们还将使用光遗传学和分子生物学技术 确定介导酒精依赖引起的痛觉过敏/痛觉过敏的大脑回路和 创伤应激，以及介导MC4R拮抗剂减轻疼痛的电路。这个问题是 及时而重要的是因为创伤后应激障碍和AUD彼此高度并存，并伴有疼痛障碍， 酒精经常被用作一种自我治疗策略，以减少创伤后应激障碍的症状和疼痛。 这项拟议工作的总体目标是：1)测试鼻腔给药的翻译潜力 用于减轻PTSD和AUD患者疼痛的黑素皮质素受体药物，以及2)识别大脑 在酒精依赖或创伤应激后，介导更高的疼痛敏感性的回路，以及 通过黑素皮质素受体药物介导疼痛减轻的回路。

U.S. military veterans are more frequently diagnosed with post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) than the general population, and individuals with PTSD often self-medicate with alcohol in amounts that worsen health outcomes (e.g., pain), leading to a huge health and financial burden in the United States. Pain is highly co-morbid with PTSD and AUD, but strategies are not adequate for treating individuals living with two or more of these diagnoses, and the neurobiological mechanisms underlying these disorders are not well defined. The ultimate goal of the work proposed here is to improve Veteran health and quality of life by guiding therapeutic strategies that reduce pain in individuals with PTSD and/or AUD. This project falls within the scope of the V.A. Office of Research and Development Biomedical Laboratory Research and Development (BLR&D) Service goal to fund preclinical biomedical and behavioral studies of disorders important for Veteran health. More specifically, this innovative and clinically relevant application proposes work that will examine the neurobiological mechanisms of increased pain sensitivity in individuals that have endured traumatic stress or are dependent on alcohol. This work has clear potential to lead to significant advances in health care for Veterans. This application proposes the use of rodent models to examine the role of brain melanocortin-4 receptor (MC4R) signaling in hyperalgesia/allodynia in individuals that are alcohol-dependent or have been traumatically stressed. We will use behavioral pharmacology techniques to test the therapeutic potential of intra-nasally delivered MC4R antagonists for reducing pain, relative to systemic morphine (the clinical gold standard). We will also use optogenetics and molecular biology techniques to identify the brain circuitry that mediates hyperalgesia/allodynia induced by alcohol dependence and traumatic stress, as well as the circuitry that mediates pain reduction by MC4R antagonists. This question is timely and important because PTSD and AUD are highly co-morbid with each other and with pain disorders, and alcohol is often used as a self-medication strategy to reduce PTSD symptoms and pain. The overall goals of the proposed work are to 1) test the translational potential of intra-nasal delivery of melanocortin receptor drugs for reducing pain in individuals with PTSD and AUD, and 2) identify the brain circuitry that mediates higher pain sensitivity after alcohol dependence or traumatic stress, as well as the circuitry that mediates pain reduction by melanocortin receptor drugs.