Abolition of morphine-immunosuppression in mice lacking the μ-opioid receptor gene
Abolition of morphine-immunosuppression in mice lacking the μ-opioid receptor gene
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DOI：
10.1073/pnas.95.11.6326
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发表时间：
1998-05-26
影响因子：
11.1
通讯作者：
Kieffer, BL
中科院分区：
文献类型：
--
作者：
Gavériaux-Ruff, C;Matthes, HWD;Kieffer, BL
阿片类药物是一种有效的镇痛和成瘾化合物。它们还作用于免疫反应，吗啡，原型阿片，已被反复描述为免疫抑制药物。药理学研究表明，阿片类药物对免疫的抑制作用是由多个阿片受体位点介导的，但分子证据仍然难以捉摸。最近，已经克隆了编码μ-（莫尔）、δ-和κ-阿片受体的三种基因。为了研究μ-阿片受体是否在功能上参与体内吗啡免疫抑制，我们研究了莫尔基因遗传破坏的小鼠的免疫应答。在没有药物的情况下，野生型和突变小鼠之间在大量的免疫学终点方面没有差异，这表明缺乏MOR编码的蛋白对免疫状态几乎没有影响。慢性吗啡给药诱导轻度小鼠淋巴器官萎缩，胸腺中CD 4（+）CD 8（+）细胞的比例降低，自然杀伤细胞活性显著降低。吗啡治疗后，在MOR缺陷小鼠中没有观察到这些作用。这表明，莫尔基因产物代表了吗啡对免疫系统作用的主要分子靶标。因为我们以前的研究MOR缺陷小鼠表明，这种受体蛋白也负责吗啡镇痛，奖励和身体依赖，目前的结果意味着，MOR靶向治疗药物，开发用于治疗疼痛或阿片类药物成瘾可能伴随着影响免疫反应。
Opiates are potent analgesic and addictive compounds. They also act on immune responses, and morphine, the prototypic opiate, has been repeatedly described as an immunosuppressive drug. Pharmacological studies have suggested that the inhibitory action of opiates on immunity is mediated by multiple opioid receptor sites but molecular evidence has remained elusive. Recently, three genes encoding mu-(MOR), delta-, and kappa-opioid receptors have been cloned. To investigate whether the mu-opioid receptor is functionally implicated in morphine immunosuppression in vivo, we have examined immune responses of mice with a genetic disruption of the MOR gene. In the absence of drug, there was no difference between wild-type and mutant mice with regard to a large number of immunological endpoints, suggesting that the lack of MOR-encoded protein has little consequence on immune status. Chronic morphine administration induced lymphoid organ atrophy, diminished the ratio of CD4(+)CD8(+) cells in the thymus and strongly reduced natural killer activity in mild-type mice. None of these effects was observed in MOR-deficient mice after morphine treatment. This demonstrates that the MOR gene product represents a major molecular target for morphine action on the immune system. Because our previous studies of MOR-deficient mice have shown that this receptor protein is also responsible for morphine analgesia, reward, and physical dependence, the present results imply that MOR-targeted therapeutic drugs that are developed for the treatment of pain or opiate addiction may concomitantly influence immune responses.