Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene
Loss of morphine-induced analgesia, reward effect and withdrawal symptoms in mice lacking the mu-opioid-receptor gene
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DOI：
10.1038/383819a0
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发表时间：
1996-10-31
期刊：
影响因子：
64.8
通讯作者：
Kieffer, BL
中科院分区：
文献类型：
--
作者：
Matthes, HWD;Maldonado, R;Kieffer, BL
尽管在寻找用于疼痛治疗的安全、有效且无成瘾性的阿片类药物方面付出了巨大努力，但吗啡仍然是现代医学中最有价值的止痛药。阿片类药物通过三种阿片受体类别（μ、δ和κ）发挥其药理作用，这三种受体的基因已被克隆。现在可以利用遗传学方法来阐明每种受体在体内阿片类药物功能中的作用。在此，我们通过同源重组破坏小鼠的μ - 阿片受体基因，发现这些动物的阿片系统内没有明显的行为异常或主要的代偿性变化。对吗啡行为效应的研究表明，缺乏μ受体消除了吗啡的镇痛作用，以及位置偏好行为和身体依赖性。我们没有观察到与吗啡激活δ或κ受体相关的行为反应，尽管这些受体存在且能结合阿片类配体。我们得出结论，μ - 阿片受体基因产物是体内吗啡的分子靶点，并且它是阿片系统中吗啡作用的必要组成部分。
DESPITE tremendous efforts in the search for safe, efficacious and non-addictive opioids for pain treatment, morphine remains the most valuable painkiller in contemporary medicine. Opioids exert their pharmacological actions through three opioid-receptor classes(1,2), mu, delta and kappa, whose genes have been cloned(3). Genetic approaches are now available to delineate the contribution of each receptor in opioid function in vivo. Here we disrupt the mu-opioid-receptor gene in mice by homologous recombination and find that there are no overt behavioural abnormalities or major compensatory changes within the opioid system in these animals. Investigation of the behavioural effects of morphine reveals that a lack of mu receptors abolishes the analgesic effect of morphine, as well as place-preference activity and physical dependence. We observed no behavioural responses related to delta- or kappa-receptor activation with morphine, although these receptors are present and bind opioid ligands. We conclude that the mu-opioid-receptor gene product is the molecular target of morphine in vivo and that it is a mandatory component of the opioid system for morphine action.