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

项目摘要 大约65%的退伍军人在过去3个月内报告疼痛，超过50%的退伍军人在VHA接受护理 机构报告慢性疼痛。慢性疼痛综合征在女性退伍军人和成年人中更常见 24岁以下的美军约占10%，但人们对神经生物学差异知之甚少 在青春期和成年期开始的慢性疼痛的介质。一线治疗方法 在过去的几十年里，慢性疼痛一直是阿片类药物，但这种方法已经创造了一个主要的健康 由处方阿片类药物滥用率高、疼痛患者中阿片类药物使用障碍率高、 从处方类阿片开始的娱乐性类阿片使用者的比例，以及类阿片相关死亡的高比例。 在这里，我们提出了实验，测试黑皮质素-4受体（MC4Rs）作为治疗慢性 炎性疼痛。MC4R广泛分布于CNS中，具有内源性激动剂（α-黑素细胞受体）。 刺激激素）和内源性拮抗剂（刺豚鼠相关蛋白）配体。MC4R及其配体是 在上行和下行疼痛通路中表达，包括在中央杏仁核（CeA）和 中脑导水管周围灰质（PAG）。腹外侧PAG（vlPAG）接收密集的CeA输入并馈入 下行痛觉调制回路我们实验室和其他实验室的先前工作表明，中央MC4R阻滞 它本身的抗疼痛作用，而且它增强了急性吗啡的镇痛作用， 发展对慢性吗啡镇痛作用的耐受性，并阻断吗啡戒断- 诱发痛觉过敏。 在这里，我们的总体假设是，大脑MC4Rs是一个有前途的新的非阿片类药物靶点，用于减少 慢性炎性疼痛患者的伤害感受。我们将在补充中检验这一假设。 目的是使用会聚技术1）检查慢性炎性疼痛的神经生物学效应 在男性和女性的成年期或青春期开始，2）测试鼻内给药的效果 递送的MC4R拮抗剂对慢性炎性疼痛的作用。具体目标1将检验慢性病 炎症性疼痛产生伤害感受和疼痛回避的年龄特异性变化，CeA MC4R表达 和青少年和成年雄性和雌性大鼠中的CeA-vlPAG回路活性。具体目标2将测试 预测CeA内MC4R拮抗作用和CeA-vlPAG回路刺激拯救炎性 在青春期和成年雄性和雌性大鼠中的痛觉过敏和疼痛回避。第3章测试 预测鼻内MC4R拮抗剂可挽救炎性痛觉过敏并增强吗啡 抗痛觉过敏作用。

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.