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

基本信息

批准号：
10609789
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
项目类别：
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/10609789
关键词：
ART protein Acute Adolescence Adolescent Adult Affect Age 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&apos s Adjuvant Health Human Hyperalgesia Hypersensitivity Individual Inflammatory Infusion procedures Injections Intraventricular Injections Joints Ligands Locomotion Male Adolescents Mechanics Mediating Mediator Melanocortin 4 Receptor Military Personnel Modeling Morphine Musculoskeletal Neurobiology Nociception Opioid Pain Pathway interactions Pharmaceutical Preparations Prevalence Rattus Receptor Signaling Recreation Reporting Rodent Services Slice Syndrome Techniques Testing Thermal Hyperalgesias Translations Veterans Withdrawal Work aging population 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

项目摘要

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.

项目概要大约 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 接受护理设施报告慢性疼痛。慢性疼痛综合症在女性退伍军人和成年人中更为常见 24 岁以下的军人约占美国军人的 10%，但人们对神经生物学方面的差异知之甚少始于青春期与成年期的慢性疼痛的介质。一线治疗方法过去几十年来的慢性疼痛一直是阿片类药物，但这种方法已经造成了重大健康问题危机的定义是处方阿片类药物滥用率高、疼痛患者阿片类药物使用障碍率高、娱乐性阿片类药物使用者开始使用处方阿片类药物的比例，以及与阿片类药物相关的死亡率很高。在这里，我们提出了测试黑皮质素 4 受体 (MC4R) 作为慢性病治疗靶点的实验。炎症性疼痛。 MC4R广泛分布于中枢神经系统，具有内源性激动剂（α-黑素细胞- 刺激激素）和内源性拮抗剂（刺豚鼠相关蛋白）配体。 MC4R及其配体是在上升和下降疼痛通路中表达，包括中央杏仁核 (CeA) 和导水管周围灰质（PAG）。腹外侧 PAG (vlPAG) 接收密集的 CeA 输入并馈送到下行疼痛调制电路。我们实验室和其他人之前的工作表明，中央 MC4R 封锁已它本身的抗痛作用，而且它还增强了急性吗啡的镇痛作用，阻断了对长期吗啡的镇痛作用产生耐受性，并阻止吗啡戒断- 诱发痛觉过敏。在这里，我们的总体假设是大脑 MC4R 是一种有前途的新型非阿片类药物靶点，可减少患有慢性炎性疼痛的个体的伤害感受。我们将以互补的方式检验这个假设目标是使用聚合技术来 1）检查慢性炎症疼痛的神经生物学影响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 MC4R 拮抗剂治疗慢性炎症疼痛。具体目标 1 将检验慢性病的预测炎症性疼痛会导致伤害感受和疼痛避免、CeA MC4R 表达的年龄特异性变化以及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 电路刺激可挽救炎症青少年和成年雄性和雌性大鼠的痛觉过敏和疼痛回避。具体目标 3 将测试预测鼻内 MC4R 拮抗剂可挽救炎症性痛觉过敏并增强吗啡的作用抗痛觉过敏作用。

项目成果

期刊论文数量（14）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Quantitative Analysis of Gene Expression in RNAscope-processed Brain Tissue.

RNAscope 处理的脑组织中基因表达的定量分析。

DOI：
10.21769/bioprotoc.4580
发表时间：
2023
期刊：
Bio-protocol
影响因子：
0.8
作者：
Secci,MariaE;Reed,Tanner;Quinlan,Virginia;Gilpin,NicholasW;Avegno,ElizabethM
通讯作者：
Avegno,ElizabethM

Reciprocal midbrain-extended amygdala circuit activity in preclinical models of alcohol use and misuse.

DOI：
10.1016/j.neuropharm.2021.108856
发表时间：
2022-01-01
期刊：
Neuropharmacology
影响因子：
4.7
作者：
Avegno EM;Gilpin NW
通讯作者：
Gilpin NW

Chronic nicotine increases alcohol self-administration in adult male Wistar rats.

DOI：
10.1007/s00213-020-05669-8
发表时间：
2021-01
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Montanari C;Secci ME;Driskell A;McDonald KO;Schratz CL;Gilpin NW
通讯作者：
Gilpin NW

Pramipexole treatment attenuates mechanical hypersensitivity in male rats experiencing chronic inflammatory pain.

DOI：
10.1016/j.neuropharm.2022.108976
发表时间：
2022-05-01
期刊：
NEUROPHARMACOLOGY
影响因子：
4.7
作者：
Edwards, Scott;Callicoatte, Chelsea N.;Barattini, Angela E.;Cucinello-Ragland, Jessica A.;Melain, Alex;Edwards, Kimberly N.;Gilpin, Nicholas W.;Avegno, Elizabeth M.;Pahng, Amanda R.
通讯作者：
Pahng, Amanda R.

Positive allosteric modulation of the cannabinoid type-1 receptor (CB1R) in periaqueductal gray (PAG) antagonizes anti-nociceptive and cellular effects of a mu-opioid receptor agonist in morphine-withdrawn rats.