Targeting melanocortin-4 receptors to reduce pain in U.S. Veterans

靶向黑皮质素 4 受体以减轻美国退伍军人的疼痛

• 批准号: 10260950
• 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 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260950
• 关键词: ART protein; Acute; Adolescence; Adolescent; Adult; Affect; Age; Aging; Agonist; Alcohol withdrawal syndrome; American; Amygdaloid structure; Analgesics; Animals; Arthritis; Biochemistry; Brain; Caring; Chronic; Chronic inflammatory pain; Development; Dose; Drug Delivery Systems; Electrophysiology (science); Feeds; Female; Freund' s Adjuvant; Health; Human; Hyperalgesia; Hypersensitivity; Individual; Inflammatory; Infusion procedures; Injections; Intranasal Administration; Intraventricular Injections; Joints; Ligands; Locomotion; Male Adolescents; Mechanics; Mediating; Mediator of activation protein; Melanocortin 4 Receptor; Military Personnel; Modeling; Morphine; Musculoskeletal; Neurobiology; Nociception; Opioid; Pain; Pathway interactions; Pharmaceutical Preparations; Prevalence; Rattus; Receptor Signaling; Reporting; Rodent; Services; Slice; Syndrome; Techniques; Testing; Thermal Hyperalgesias; Translations; Veterans; Withdrawal; Work; alpha-Melanocyte stimulating hormone; antagonist; chronic pain; chronic pain management; conditioned place preference; cost; disability; experimental study; foot; inflammatory pain; male; midbrain central gray substance; non-opioid analgesic; novel; opioid mortality; opioid use disorder; opioid user; optogenetics; pain patient; pain reduction; prescription opioid; prescription opioid abuse; receptor expression; sex; side effect

Project Summary Approximately 65% of Veterans report pain in the last 3 months, and >50% of Veterans receiving care at VHA facilities report chronic pain. Chronic pain syndromes are more common among female veterans, and adults under age 24 comprise ~10% of the U.S. military, but little is known about differences in neurobiological mediators of chronic pain that starts in adolescence versus adulthood. The first-line treatment approach for chronic pain over the last few decades has been opioid drugs, but this approach has created a major health crisis defined by high rates of prescription opioid abuse, high rates of opioid use disorder in pain patients, high rates of recreational opioid users starting with prescription opioids, and high rates of opioid-related deaths. Here, we propose experiments that test melanocortin-4 receptors (MC4Rs) as a target for treatment of chronic inflammatory pain. MC4Rs are widely distributed in CNS, with endogenous agonist (alpha-melanocyte- stimulating hormone) and endogenous antagonist (agouti-related protein) ligands. MC4R and its ligands are expressed in ascending and descending pain pathways, including in central amygdala (CeA) and periaqueductal gray (PAG). The ventrolateral PAG (vlPAG) receives dense CeA input and feeds into descending pain modulation circuits. Prior work by our lab and others showed that central MC4R blockade has anti-pain effects of its own, and also that it potentiates the analgesic effects of acute morphine, blocks the development of tolerance to the analgesic effects of chronic morphine, and blocks morphine withdrawal- induced hyperalgesia. Here, our overarching hypothesis is that brain MC4Rs are a promising novel non-opioid target for reducing nociception in individuals living with chronic inflammatory pain. We will test this hypothesis in complementary aims that use convergent techniques to 1) examine the neurobiological effects of chronic inflammatory pain that starts during adulthood or adolescence in males and females, and 2) test the effect of intranasally delivered MC4R antagonist on chronic inflammatory pain. Specific Aim 1 will test the prediction that chronic inflammatory pain produces age-specific changes in nociception and pain avoidance, CeA MC4R expression and CeA-vlPAG circuit activity in adolescent and adult male and female rats. Specific Aim 2 will test the prediction that intra-CeA MC4R antagonism and CeA-vlPAG circuit stimulation rescue inflammatory hyperalgesia and pain avoidance in adolescent and adult male and female rats. Specific Aim 3 will test the predictions that intra-nasal MC4R antagonism rescues inflammatory hyperalgesia and enhances morphine anti-hyperalgesic effects.

项目摘要 大约65％的退伍军人报告了过去3个月的疼痛，> 50％的退伍军人在VHA接受护理 设施报告慢性疼痛。慢性疼痛综合征在女性退伍军人和成年人中更为常见 24岁以下占美国军队的约10％，但对神经生物学的差异知之甚少 慢性疼痛的介体始于青春期与成年。用于的一线治疗方法 在过去的几十年中，慢性疼痛一直是阿片类药物，但是这种方法创造了重要的健康状况 高处方阿片类药物滥用发生率，疼痛患者的阿片类药物使用障碍率高，高危机定义 从处方阿片类药物开始的休闲阿片类药物使用者和阿片类药物相关的死亡率高。 在这里，我们提出了测试黑素皮质素-4受体（MC4R）作为慢性治疗的靶标的实验 炎症性疼痛。 MC4R与内源性激动剂（α-甲状腺细胞 - 刺激激素）和内源性拮抗剂（与Agouti相关的蛋白质）配体。 MC4R及其配体是 在上升和下降的疼痛途径中表达，包括中央杏仁核（CEA）和 灰灰色（PAG）。腹外侧PAG（VLPAG）接收密集的CEA输入，并进食 下降疼痛调节电路。我们的实验室和其他人的事先工作表明，中央MC4R封锁有 其自身的抗呼吸作用，也增强了急性吗啡的镇痛作用，阻止了 发展对慢性吗啡的镇痛作用的耐受性，并阻止吗啡戒断 - 诱导的痛觉过敏。 在这里，我们的总体假设是大脑MC4RS是一个有希望的新型非阿片类药物靶标的减少靶标 患有慢性炎症性疼痛的人的伤害感受。我们将在互补中检验这一假设 使用收敛技术到1）检查慢性炎症性疼痛的神经生物学作用 从男性和女性的成年或青春期开始，2）测试鼻内的影响 在慢性炎症性疼痛方面提供了MC4R拮抗剂。特定目标1将测试慢性的预测 炎症性疼痛会导致年龄特异性的伤害感和避免疼痛，CEA MC4R表达 以及青少年和成年男性和雌性大鼠的CEA-VLPAG电路活性。具体目标2将测试 预测CEA内MC4R拮抗作用和CEA-VLPAG电路刺激促进炎症 青春期和成年男性和雌性大鼠的痛苦和避免疼痛。特定目标3将测试 鼻腔内MC4R拮抗作用的预测可以挽救炎症性痛觉过敏并增强吗啡 抗高质量作用。