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.

美国退伍军人更经常被诊断出患有创伤后应激障碍（PTSD）和酒精 使用障碍（AUD）比一般人群，而患有PTSD的人通常会用酒精自我治疗 恶化健康成果的金额（例如疼痛），导致了巨大的健康和经济负担 国家。疼痛与PTSD和AUD高度合并，但策略不足以治疗个体 与这些诊断中的两个或多个生活一起生活，这些疾病的神经生物学机制是 定义不当。这里提出的工作的最终目标是通过 指导治疗策略，以减轻PTSD和/或AUD患者的疼痛。 该项目属于V.A.的范围。研发办公室生物医学实验室 研发（BLR＆D）服务目标，以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 提出的工作将检查个体增加疼痛敏感性的神经生物学机制 忍受了创伤应力或依赖酒精。这项工作有明显的潜力导致 退伍军人的医疗保健取得了重大进展。该应用建议使用啮齿动物模型 检查脑黑素皮质素-4受体（MC4R）信号在Hyperatusia/Allodynia中的作用 依赖酒精或已受到创伤。我们将使用行为药理学技术 为了测试临终内传递的MC4R拮抗剂的治疗潜力，以减轻疼痛，相对于 系统性吗啡（临床黄金标准）。我们还将使用光遗传学和分子生物学技术 确定介导酒精依赖性诱导的痛觉过敏/异常性疾病的脑电路 创伤性应力，以及介导MC4R拮抗剂减轻疼痛的回路。这个问题是 及时和重要 酒精通常被用作减轻PTSD症状和疼痛的一种自我药物策略。 拟议工作的总体目标是1）测试鼻内交付的翻译潜力 黑色皮质素受体药物可减少PTSD和AUD的个体疼痛，以及2）识别大脑 在酒精依赖或创伤应力后介导较高疼痛敏感性的电路以及 通过黑色素皮质受体药物减轻疼痛的电路。