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

项目摘要 大约65%的退伍军人报告在过去的3个月中感到疼痛，50%的退伍军人在VHA接受护理 医疗机构报告慢性疼痛。慢性疼痛综合征在女性退伍军人和成年人中更常见 24岁以下约占美国军队的10%，但人们对神经生物学的差异知之甚少 从青春期开始的慢性疼痛的中介物，而不是成年。本病的一线治疗方法 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重大的健康 危机定义为处方阿片类药物滥用的高比率，疼痛患者的阿片类药物使用障碍的高比率， 娱乐性阿片类药物使用者从处方阿片类药物开始的比率，以及与阿片类药物相关的高死亡率。 在这里，我们提出了测试黑素皮质素-4受体(MC4Rs)作为治疗慢性阻塞性肺疾病的靶点的实验。 炎症性疼痛。MC4Rs广泛分布于中枢神经系统，具有内源性激动剂(α-黑素细胞-α)。 刺激素)和内源性拮抗剂(刺鼠相关蛋白)配体。MC4R及其配体是 表达于上行和下行痛觉通路，包括中央杏仁核(CEA)和 导水管周围灰质(PAG)。腹外侧方PAG(VlPAG)接受密集的CEA输入，并馈入 下行疼痛调制电路。我们实验室和其他人之前的工作表明，中央MC4R封锁 它本身的止痛作用，也就是它增强了急性吗啡的镇痛作用，阻断了 对慢性吗啡的止痛作用产生耐受性，并阻止吗啡戒断- 诱发性痛觉过敏。 在这里，我们的主要假设是，大脑MC4R是一个有希望的新的非阿片类药物靶点 慢性炎症性疼痛患者的伤害性感受。我们将在互补性中检验这一假设 旨在使用融合技术1)检查慢性炎症性疼痛的神经生物学效应 这在成年或青春期开始，在男性和女性中，2)测试鼻腔注射 使用MC4R拮抗剂治疗慢性炎症性疼痛。特定目标1将测试慢性疾病的预测 炎症性疼痛在痛觉和疼痛回避中产生年龄特异性变化，CEA MC4R表达 青春期和成年雌雄大鼠的CEA-vlPAG环路活性。《特定目标2》将测试 CEA内MC4R拮抗和CEA-vlPAG回路刺激挽救炎症反应的预测 青春期和成年期雄性和雌性大鼠的痛觉过敏和疼痛回避。《特定目标3》将测试 预测鼻腔注射MC4R拮抗剂可挽救炎症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.