Opioid abuse is a rapidly growing public health crisis in the USA. Despite extensive research in the past decades, little is known about the etiology of opioid addiction or the neurobiological risk factors that increase vulnerability to opioid use and abuse. Recent studies suggest that the type 2 metabotropic glutamate receptor (mGluR2) is critically involved in substance abuse and addiction. In the present study, we evaluated whether low-mGluR2 expression may represent a risk factor for the development of opioid abuse and addiction using transgenic mGluR2-knockout (mGluR2-KO) rats. Compared to wild-type controls, mGluR2-KO rats exhibited higher nucleus accumbens (NAc) dopamine (DA) and locomotor responses to heroin, higher heroin self-administration and heroin intake, more potent morphine-induced analgesia and more severe naloxone-precipitated withdrawal symptoms. In contrast, mGluR2-KO rats displayed lower motivation for heroin self-administration under high price progressive-ratio (PR) reinforcement conditions. Taken together, these findings suggest that mGluR2 may play an inhibitory role in opioid action, such that deletion of this receptor results in an increase in brain DA responses to heroin and in acute opioid reward and analgesia. Low-mGluR2 expression in the brain may therefore be a risk factor for the initial development of opioid abuse and addiction.

中文翻译：

---

2型代谢型谷氨酸受体的缺失增加了转基因大鼠中海洛因滥用的脆弱性。

阿片类药物滥用是美国迅速增长的公共卫生危机。尽管在过去的几十年中进行了广泛的研究，但对阿片类药物成瘾的病因学或增加阿片类药物使用和滥用的脆弱性的神经生物学危险因素知之甚少。最近的研究表明，2型代谢型谷氨酸受体（mGluR2）严重参与了药物滥用和成瘾。在本研究中，我们评估了低mGluR2表达是否可能代表使用转基因mGluR2-敲除（mGluR2-KO）大鼠的阿片类药物滥用和成瘾的发展的危险因素。与野生型对照组相比，mGluR2-KO大鼠表现出较高的伏隔核（NAc）多巴胺（DA）和对海洛因的运动反应，较高的海洛因自我给药和海洛因摄入量，吗啡引起的镇痛作用更强，纳洛酮引起的戒断症状更为严重。相比之下，mGluR2-KO大鼠在高价格递增比率（PR）增强条件下显示出较低的海洛因自我给药动机。综上，这些发现表明，mGluR2可能在阿片样物质的作用中起抑制作用，从而使该受体的缺失导致脑对海洛因的DA反应增加以及急性阿片样物质的奖励和镇痛。因此，大脑中mGluR2的低表达可能是阿片类药物滥用和成瘾初期发展的危险因素。这些发现表明，mGluR2可能在阿片样物质的作用中起抑制作用，从而使该受体的缺失导致脑对海洛因的DA反应增加以及急性阿片样物质的奖励和镇痛。因此，大脑中低mGluR2表达可能是阿片类药物滥用和成瘾初期发展的危险因素。这些发现表明，mGluR2可能在阿片样物质的作用中起抑制作用，从而使该受体的缺失导致脑对海洛因的DA反应增加以及急性阿片样物质的奖励和镇痛。因此，大脑中低mGluR2表达可能是阿片类药物滥用和成瘾初期发展的危险因素。