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

靶向 Melanocortin-4 受体以减轻美国退伍军人的疼痛

• 批准号: 9241075
• 负责人: NICHOLAS WARREN GILPIN
• 金额: --
• 依托单位: SOUTHEAST LOUISIANA VETERANS HEALTH CARE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9241075
• 关键词: ART protein; Absence of pain sensation; Agonist; Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcohols; Amygdaloid structure; Analgesics; Animals; Brain; Brain region; Chronic; Clinic; Data; Dependence; Diagnosis; Disease; Drug Delivery Systems; Drug Receptors; Emotional; Exhibits; Funding; Future; General Population; Goals; Gold; Health; Healthcare; Histology; Human; Hyperalgesia; Hypersensitivity; Imaging Techniques; Individual; Laboratory Research; Lead; Ligands; Mediating; Melanocortin 4 Receptor; Military Personnel; Modeling; Molecular Biology Techniques; Morphine; Nociception; Nose; Opiates; Opioid; Opioid Receptor; Outcome; Pain; Pain Disorder; Pain Threshold; Pain management; Patients; Penetrance; Perception; Pharmaceutical Preparations; Pharmacology; Physiological; Population; Post-Traumatic Stress Disorders; Quality of life; Rattus; Receptor Signaling; Reporting; Rodent; Rodent Model; Role; Self Medication; Services; Signal Transduction; Site; Spinal; Stress; Symptoms; Techniques; Testing; Therapeutic; Time; United States; Veterans; Visceral; Work; acute stress; alcohol use disorder; allodynia; alpha-Melanocyte stimulating hormone; behavioral pharmacology; behavioral study; brain circuitry; chronic pain; clinically relevant; combat; falls; improved; innovation; laboratory development; mechanical allodynia; melanocortin receptor; midbrain central gray substance; neurobiological mechanism; optogenetics; pain inhibition; pre-clinical; receptor; receptor function; research and development; response; therapeutic evaluation; therapeutic target

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.

美国退伍军人更常被诊断患有创伤后应激障碍（PTSD）和酗酒 使用障碍（AUD）高于一般人群，患有创伤后应激障碍（PTSD）的人经常用酒精进行自我治疗 导致健康结果恶化（例如疼痛）的量，给美国带来巨大的健康和经济负担 国家。疼痛与 PTSD 和 AUD 高度共存，但策略不足以治疗个体 患有两种或多种这些诊断，并且这些疾病背后的神经生物学机制是 没有明确定义。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 指导减轻 PTSD 和/或 AUD 患者疼痛的治疗策略。 该项目属于 V.A. 的范围。研发办公室生物医学实验室 研究与开发 (BLR&D) 服务目标是资助临床前生物医学和行为研究 对退伍军人健康很重要的疾病。更具体地说，这种创新且与临床相关的应用 提出了研究个体疼痛敏感性增加的神经生物学机制的工作 遭受过创伤性压力或依赖酒精的人。这项工作有明显的潜力 退伍军人医疗保健方面取得重大进展。该申请建议使用啮齿动物模型来 检查大脑黑皮质素 4 受体 (MC4R) 信号在个体痛觉过敏/异常性疼痛中的作用 酒精依赖者或遭受过创伤性压力。我们将使用行为药理学技术 测试鼻内递送 MC4R 拮抗剂减轻疼痛的治疗潜力，相对于 全身吗啡（临床金标准）。我们还将使用光遗传学和分子生物学技术 识别介导酒精依赖引起的痛觉过敏/异常性疼痛的大脑回路，以及 创伤性应激，以及通过 MC4R 拮抗剂介导减轻疼痛的电路。这个问题是 及时且重要，因为 PTSD 和 AUD 彼此高度共存，并且与疼痛障碍高度共存， 酒精通常被用作一种自我治疗策略，以减轻创伤后应激障碍（PTSD）症状和疼痛。 拟议工作的总体目标是 1）测试鼻内递送的转化潜力 用于减轻 PTSD 和 AUD 患者疼痛的黑皮质素受体药物，以及 2) 识别大脑 在酒精依赖或创伤性应激后介导更高的疼痛敏感性的电路，以及 通过黑皮质素受体药物介导减轻疼痛的电路。