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Molecular pharmacological study on the roles of the central noradreneric neurosis in the higher central actions of morphine

中枢去甲肾上腺素神经症在吗啡高级中枢作用中作用的分子药理学研究

基本信息

批准号：
14370743
负责人：
SATOH Masamichi
金额：
$ 7.68万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2003
项目状态：
已结题

项目摘要

μ-Opioid receptor, a receptor far morphine, is intensely expressed in the noradrenergic neurons located in the locus coeruleus.. These neurons project into various brain regions including the cerebral cortex, hippocampus and amygdala, and are implicated in memory, emotion and stress responses. However, the molecular bases for the regulation of memory, emotion and stress responses through the opioid system remain to be elucidated. In this study, we generated the genetically modified mouse line in which μ-opioid receptors are expressed only in the not adrenergic neurons by means of the crossbreeding between the μ-opioid receptor KO mouse and the transgenic mouse in which the expression of human μ-opioid receptor gene is regulated by DBH (dopamine β-hydroxyrase) promoter. Using this newly generated mouse line, we showed that the μ-opioid receptors expressed in the noradrenergic neurons are involved in the regulation of stress responses, such as the escape behavior and corticosteroid hormone release induced by the stress. In addition, using the μ-opioid receptor KO mice, we demonstrated that most of the analgesic effect of buprenorphine, one of the analgesics clinically used in Japan, is mediated by μ-opioid receptors. These findings are considered to be useful for the understanding of the roles of μ-opioid receptors in the stress responses and for the improvement of clinical use of buprenorphine.

阿片μ受体是吗啡的受体，在蓝斑的去甲肾上腺素能神经元中有强表达。这些神经元投射到大脑的各个区域，包括大脑皮层、海马和杏仁核，并与记忆、情绪和压力反应有关。然而，通过阿片系统调节记忆、情绪和应激反应的分子基础仍有待阐明。本研究利用多巴胺β羟化酶（DBH）启动子调控人μ阿片受体基因表达的转基因小鼠与μ阿片受体基因敲除小鼠杂交，建立了μ阿片受体仅在非肾上腺素能神经元表达的转基因小鼠。利用这一新的小鼠细胞系，我们发现去甲肾上腺素能神经元中表达的μ阿片受体参与了应激反应的调节，如应激诱导的逃避行为和皮质类固醇激素的释放。此外，使用μ-阿片受体KO小鼠，我们证明了丁丙诺啡（日本临床使用的镇痛药之一）的大部分镇痛作用是由μ-阿片受体介导的。这些结果有助于了解μ阿片受体在应激反应中的作用，并有助于丁丙诺啡的临床应用。