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

项目摘要。根据疾病控制和预防中心的数据，有70237种药物 2017年美国报告的过量死亡人数超过每天130人，其中67.8%涉及阿片类药物 [1]。虽然有治疗这种疾病的药物(例如美沙酮、亚伯酮和缓释剂 纳曲酮)，复发率仍然高得惊人[2-4]。显然，需要新的方法。为此，我们 认识到上瘾不仅包括劫持奖励途径，也包括劫持需要途径[5]。AS 因此，我们假设，寻求和服用海洛因应该通过外周刺激胰升糖素来减少- 类似肽-1受体(GLP-1R)的“饱腹感”途径。作为支持，GLP-1R通路的激活已经被 被证明不仅能抑制可口的糖果、口渴时的水和缺钠时的盐的摄取，而且 对酒精、尼古丁和可卡因也有反应[6-12]。在这里，我们第一次展示了 使用GLP-1R激动剂也可以减少海洛因的摄取、寻找和药物诱导的恢复。 老鼠。这项应用的目的是测试使用GLP-1R激动剂治疗是否可以减少乳腺癌的复发 患有阿片类药物使用障碍的人(OUD)。使用GLP-1R激动剂的一个优点是 配方已经被批准用于治疗肥胖症和2型糖尿病[13，14]。UG3阶段目标G1 将进行一项随机、双盲、安慰剂对照的试验研究，以确定每天一次 使用短效GLP-1R激动剂利拉鲁肽治疗可以安全有效地减少饥饿感和 住院治疗的患者对药物提示的大脑反应。UG3阶段目标G2将使用 建立完善的动物模型来测试风险更大、作用时间更长、但更 有效，GLP-1R激动剂，Semagluide，在海洛因寻找和线索/药物/应激诱导的恢复中有效。 里程碑：(1)证明批准剂量的利拉鲁肽安全有效，可减少饥饿感和大脑 同时接受咨询的OUD住院治疗患者对药物线索的反应 仅(CO)或咨询+丁丙诺啡/纳曲酮(BUP/NA)；(2)验证赛马路德安全有效 在减少线索/药物/压力诱导的海洛因寻找的动物模型中。如果达到了这些里程碑，UH3 阶段目标H1将在#年进行一项双臂、伪随机、安慰剂对照的多部位临床试验 接受OUD检查的门诊患者测试赛马路德与安慰剂治疗是否会将复发率降低到180 CO和咨询+BUP/NA治疗的天数。UH3阶段目标H2将使用动物模型 进一步探讨赛马路德预防海洛因自主给药的有效性和有用性 例如，减少正在进行的海洛因自我给药，或作为非阿片类药物的“护理桥梁”。如果我们的 假设得到支持，我们将证明使用GLP-1R激动剂治疗可以安全有效地减少 阿片类药物在大鼠和人类中的渴求、寻找和复发，为完全多部位阶段提供了第二个指征 III临床试验，我们将为FDA的批准奠定临床前和临床基础。

Project Summary. According to the Centers for Disease Control and Prevention, there were 70,237 drug overdose deaths reported in the United States in 2017, more than 130 per day, with 67.8% involving opioids [1]. While medications are available to treat the disease (e.g., methadone, suboxone, and extended release naltrexone), relapse rates remain alarmingly high [2-4]. Clearly, new approaches are needed. To this end, we recognize that addiction involves not only hijacking of the reward pathway, but also of the need pathway [5]. As such, we posited that heroin seeking and taking should be reduced by peripheral stimulation of the glucagon- like peptide-1 receptor (GLP-1R) ‘satiety’ pathway. In support, activation of the GLP-1R pathway has been shown to inhibit not only ingestion of palatable sweets, water when thirsty, and salt when sodium deprived, but also responding for alcohol, nicotine, and cocaine in rats and mice [6-12]. Here, we show for the first time that pretreatment with a GLP-1R agonist also reduces heroin taking, seeking, and drug-induced reinstatement in rats. The objective of this application is to test whether treatment with a GLP-1R agonist can reduce relapse in humans with an opioid use disorder (OUD). One advantage of using GLP-1R agonists is that various formulations already are approved for treatment of obesity and type 2 diabetes [13, 14]. UG3 Phase Aim G1 will conduct a randomized, double blind, placebo-controlled pilot study to determine whether once daily treatment with the shorter acting GLP-1R agonist, liraglutide, can safely and effectively reduce craving and brain responses to drug cues among patients in residential treatment for an OUD. UG3 Phase Aim G2 will use well established animal models to test the efficacy and safety of a more risky, longer-acting, but more efficacious, GLP-1R agonist, semaglutide, on heroin seeking and cue/drug/stress-induced reinstatement. Milestones: (1) Demonstrate safety and efficacy liraglutide at approved doses to reduce craving and brain responses to drug cues among patients in residential treatment for OUD who also are receiving counseling only (CO) or counseling+buprenorphine/naltrexone (BUP/NA); (2) Verify that semaglutide is safe and effective in reducing cue/drug/stress-induced heroin seeking in an animal model. If these milestones are met, UH3 Phase Aim H1 will conduct a two-arm, pseudo-randomized, placebo controlled multi-site clinical trial in outpatients with an OUD to test whether treatment with semaglutide vs. placebo will reduce relapse out to 180 days in patients treated with CO and counseling+BUP/NA. UH3 Phase Aim H2 will use animal models to further probe the efficacy and usefulness of semaglutide to prevent initiation of heroin self-administration, to reduce ongoing heroin self-administration, or to serve as a non-opioid “bridge to care”, for example. If our hypotheses are supported, we will show that treatment with GLP-1R agonists can safely and effectively reduce opioid craving, seeking, and relapse in rats and humans, providing a second indication for full multi-site, Phase III clinical trials, and we will lay the preclinical and clinical groundwork for approval from the FDA.