Use of a GLP-1 Agonist to Treat Opioid Use Disorder in Rats and Man

项目总结 本行政副刊是应通知编号：NOT-DA-21-032：特别通知提交的 利息(Nosi)：芬太尼及其衍生物研究的行政补充。本副刊概述了 扩展名为“使用GLP-1激动剂治疗阿片类药物使用”的亲本5 UG3 DA050325-02的实验 大鼠和人的紊乱“。具体地说，这些研究旨在测试一种类似胰高血糖素的多肽-1 受体(GLP-1R)激动剂，被发现能安全有效地减少大鼠海洛因的摄取和寻找 家长UG3拨款，也可以安全和有效地减少线索，药物和压力诱导的恢复 寻找芬太尼。这一重点转移是至关重要的，因为在2020年前十个月，即在 在新冠肺炎大流行期间，全国几乎每个州的过量死亡人数都有所增加(见图1)[1]和 这一增长在很大程度上可以归因于与使用合成阿片类药物有关的死亡人数激增，如 芬太尼[1]。然后，特殊目标1将测试GLP-1R激动剂利拉鲁肽是否在治疗期间 禁欲和测试之前，可以减少线索诱导的芬太尼寻求以及药物和压力诱导的 在雄性SD大鼠中恢复寻求芬太尼。在这里，利拉鲁肽的剂量将被滴定为 用于治疗人类的肥胖症和2型糖尿病。具体目标2将通过测试解决安全问题 GLP-1R治疗对芬太尼引起的呼吸抑制和心血管调节障碍的影响 阿片类药物过量死亡的两个主要贡献者，以及纳洛酮催促戒断的主要原因 旧病复发的诱因。我们预测，GLP-1R激动剂利拉鲁肽的治疗将减少线索，药物， 应激诱导寻找低剂量和高剂量芬太尼，而GLP-1R激动剂不会 加重芬太尼引起的呼吸抑制、心血管调节障碍或芬太尼停药 经验丰富的老鼠。如果我们的假设被证实，我们将证明利拉鲁肽，一种非阿片类药物， 承诺作为一种安全有效的非阿片类药物治疗阿片类药物使用障碍。

PROJECT SUMMARY This administrative supplement is submitted in response to Notice Number: NOT-DA-21-032: Notice of Special Interest (NOSI): Administrative Supplements for research on fentanyl and derivatives. This supplement outlines experiments to extend the parent 5 UG3 DA050325-02 titled, “Use of a GLP-1 Agonist to Treat Opioid Use Disorder in Rats and Man”. Specifically, the studies are designed to test whether a glucagon-like peptide-1 receptor (GLP-1R) agonist, found to safely and effectively reduce heroin taking and seeking in rats in the parent UG3 grant, also can safely and effectively reduce cue-, drug-, and stress-induced reinstatement of fentanyl seeking. This shift in focus is critical because, during the first ten months of 2020, i.e., during onset of the COVID-19 pandemic, overdose deaths increased in almost every state in the nation (see Figure 1) [1] and this increase can be attributed largely to a spike in deaths related to the use of synthetic opioids such as fentanyl [1]. Specific Aim 1, then, will test whether treatment with the GLP-1R agonist, liraglutide, during abstinence and prior to test, can reduce cue-induced fentanyl seeking and drug- and stress-induced reinstatement of fentanyl seeking in male Sprague-Dawley rats. Here, the dose of liraglutide will be titrated as it is for the treatment of obesity and type two diabetes in humans. Specific Aim 2 will address safety by testing the impact of GLP-1R treatment on fentanyl-induced respiratory depression and cardiovascular dysregulation, two primary contributors to opioid overdose death, and on naloxone precipitated withdrawal, a primary precipitator of relapse. We predict that treatment with the GLP-1R agonist, liraglutide, will reduce cue-, drug-, and stress-induced seeking for both the low and the high dose of fentanyl and that the GLP-1R agonist will not exacerbate fentanyl-induced respiratory depression, cardiovascular dysregulation, or withdrawal in fentanyl experienced rats. If our hypotheses are confirmed, we will have demonstrated that liraglutide, a non-opioid, has promise as a safe and effective, non-opioid treatment for opioid use disorder.