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， 2017年美国报告的过量死亡人数每天超过130人，其中67.8%涉及阿片类药物 [1]的文件。虽然药物可用于治疗疾病（例如，美沙酮、舒宝酮和缓释剂 纳洛酮），复发率仍然高得惊人[2-4]。显然，需要采取新的办法。为此我们 认识到成瘾不仅涉及劫持奖励途径，还涉及劫持需求途径[5]。作为 因此，我们假设，通过外周刺激胰高血糖素， 如肽-1受体（GLP-1 R）“饱腹感”途径。作为支持，GLP-1 R通路的激活已被证实 显示不仅抑制可口的甜食、口渴时的水和钠缺乏时的盐的摄入， 在大鼠和小鼠中也对酒精、尼古丁和可卡因有反应[6-12]。在这里，我们第一次表明， GLP-1 R激动剂预处理也可减少海洛因服用、寻求和药物诱导的复吸， 大鼠本申请的目的是测试GLP-1 R激动剂治疗是否可以减少复发 阿片类药物使用障碍（OUD）使用GLP-1 R激动剂的一个优点是， 这些制剂已经被批准用于治疗肥胖症和2型糖尿病[13，14]。UG 3阶段目标G1 将进行一项随机、双盲、安慰剂对照的初步研究，以确定是否每日一次 使用较短效GLP-1 R激动剂利拉鲁肽治疗可安全有效地减少食欲， OUD住院治疗患者对药物提示的大脑反应。UG 3阶段目标G2将使用 建立了良好的动物模型，以测试风险更大，作用更长，但更多的有效性和安全性。 GLP-1 R激动剂Semaglutide对海洛因寻求和线索/药物/应激诱导的复吸有效。 Mild：（1）证明利拉鲁肽在批准剂量下减少食欲和大脑的安全性和有效性 接受咨询的OUD住院治疗患者对药物提示的反应 仅（CO）或咨询+丁丙诺啡/纳洛酮（BUP/NA）;（2）验证Semaglutide的安全性和有效性 在动物模型中减少线索/药物/压力诱导的海洛因寻求。如果达到这些里程碑，UH 3 阶段目标H1将进行一项两组、伪随机、安慰剂对照的多中心临床试验， 患有OUD的门诊患者，以测试semaglutide与安慰剂相比是否可将复发率降低至180 在接受CO和咨询+BUP/NA治疗的患者中，UH 3阶段目标H2将使用动物模型， 进一步探索Semaglutide预防海洛因自我给药的有效性和有用性， 例如，减少持续的海洛因自我给药，或作为非阿片类药物“通向护理的桥梁”。如果我们的 假设得到支持，我们将证明GLP-1 R激动剂治疗可以安全有效地降低 大鼠和人类的阿片类药物渴求、寻求和复发，为完整的多部位、阶段 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.