Morphine-induced mu opioid receptor trafficking enhances reward yet prevents compulsive drug use
Morphine-induced mu opioid receptor trafficking enhances reward yet prevents compulsive drug use
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DOI：
10.1002/emmm.201100144
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发表时间：
2011-07-01
影响因子：
11.1
通讯作者：
Whistler, Jennifer L.
中科院分区：
文献类型：
--
作者：
Berger, Amy Chang;Whistler, Jennifer L.
与内源性阿片相比，吗啡、海洛因和其它常滥用的阿片诱导小μ阿片受体（莫尔）运输。我们利用基因敲入小鼠表达突变体回收莫尔（RMOR），脱敏，并在响应吗啡的内在化，以表明促进莫尔贩运不仅提高吗啡的奖励，但尽管如此，减少成瘾样行为的发展。为了证明这一点，我们开发了一个新的模型，从控制到强迫性药物使用的过渡，概括了人类成瘾的许多特征，包括持续的药物寻求，尽管有不良后果和减少对替代奖励的偏好。这些行为自发出现在野生型，但不是RMOR小鼠，其强度预测恢复吗啡寻求延长禁欲后，而先前的吗啡摄入量没有。这些结果证实了先前在大鼠中的发现，即成瘾可以与奖励和消费分离。最重要的是，这些结果表明，人们可以同时减少吗啡的“成瘾性”，并通过促进激动剂诱导的莫尔运输来增强其期望的效果。
Morphine, heroin and other commonly abused opioids induce little mu opioid receptor (MOR) trafficking compared to endogenous opioids. We utilized knock-in mice expressing a mutant recycling MOR (RMOR) that desensitizes and is internalized in response to morphine to show that facilitating MOR trafficking not only enhances morphine reward but, despite this, reduces the development of addiction-like behaviours. To demonstrate this, we developed a novel model of the transition from controlled to compulsive drug use that recapitulates many features of human addiction, including persistent drug seeking despite adverse consequences and a decreased preference for alternative rewards. These behaviours emerged spontaneously in wild-type but not RMOR mice, and their intensity predicted the reinstatement of morphine seeking after extended abstinence, while prior morphine intake did not. These results confirm previous findings in the rat that addiction can be dissociated from both reward and consumption. Most importantly, these results demonstrate that one can simultaneously reduce the 'addictiveness' of morphine and enhance its desirable effects by promoting agonist-induced MOR trafficking.