Glucagon-Like Peptide-1 Receptor Agonist Treatment Does Not Reduce Abuse-Related Effects of Opioid Drugs
Glucagon-Like Peptide-1 Receptor Agonist Treatment Does Not Reduce Abuse-Related Effects of Opioid Drugs
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DOI：
10.1523/eneuro.0443-18.2019
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发表时间：
2019-03-01
期刊：
影响因子：
3.4
通讯作者：
Thomsen, Morgane
中科院分区：
文献类型：
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作者：
Bornebusch, Annika Billefeld;Fink-Jensen, Anders;Thomsen, Morgane
对阿片类药物的依赖和阿片类药物过量死亡的人数是严重和不断升级的公共卫生问题，但对许多患者来说，阿片类药物成瘾的药物辅助治疗仍然不足。胰高血糖素样肽-1（GLP-1）是一种肠道激素和神经肽，在外周组织和大脑中起作用，包括调节血糖和食物摄入。GLP-1类似物是批准的糖尿病药物，可以减少酒精、可卡因、安非他明和尼古丁对啮齿动物的强化和奖励作用。尚未报道GLP-1类似物对阿片样物质奖赏和强化作用的研究。我们评估了GLP-1受体激动剂Exendin-4（Ex 4）对雄性小鼠阿片样物质相关行为的影响，即，吗啡条件性位置偏爱（CPP）、短效合成阿片类瑞芬太尼的静脉内自我给药（IVSA）、纳洛酮促吗啡戒断、吗啡镇痛（雄性和雌性小鼠）和自发活动。Ex 4处理对吗啡诱导的CPP、戒断或过度运动没有影响。Ex 4未能减少瑞芬太尼自身给药，如果有任何增强作用的话，瑞芬太尼的增强作用在Ex 4处理的小鼠中相对于盐水似乎增加。Ex 4不显著影响镇痛。相反，Ex 4剂量依赖性地减少口服酒精自我给药，并抑制自发运动活动。总之，Ex 4没有减弱阿片类药物的成瘾相关行为效应，表明GLP-1类似物在治疗阿片类药物成瘾中不是有用的药物。迄今为止研究的阿片类药物和其他药物类别之间的这种差异可能有助于阐明GLP-1受体治疗在酒精、中枢兴奋剂和尼古丁成瘾作用中的作用机制。
Dependence on opioids and the number of opioid overdose deaths are serious and escalating public health problems, but medication-assisted treatments for opioid addiction remain inadequate for many patients. Glucagon-like pepide-1 (GLP-1) is a gut hormone and neuropeptide with actions in peripheral tissues and in the brain, including regulation of blood glucose and food intake. GLP-1 analogs, which are approved diabetes medications, can reduce the reinforcing and rewarding effects of alcohol, cocaine, amphetamine, and nicotine in rodents. Investigations on effects of GLP-1 analogs on opioid reward and reinforcement have not been reported. We assessed the effects of the GLP-1 receptor agonist Exendin-4 (Ex4) on opioid-related behaviors in male mice, i.e., morphine-conditioned place preference (CPP), intravenous self-administration (IVSA) of the short-acting synthetic opioid remifentanil, naltrexone-precipitated morphine withdrawal, morphine analgesia (male and female mice), and locomotor activity. Ex4 treatment had no effect on morphine-induced CPP, withdrawal, or hyperlocomotion. Ex4 failed to decrease remifentanil self-administration, if anything reinforcing effects of remifentanil appeared increased in Ex4-treated mice relative to saline. Ex4 did not significantly affect analgesia. In contrast, Ex4 dose dependently decreased oral alcohol self-administration, and suppressed spontaneous locomotor activity. Taken together, Ex4 did not attenuate the addiction-related behavioral effects of opioids, indicating that GLP-1 analogs would not be useful medications in the treatment of opioid addiction. This difference between opioids and other drug classes investigated to date may shed light on the mechanism of action of GLP-1 receptor treatment in the addictive effects of alcohol, central stimulants, and nicotine.