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Title: 外周电刺激调制脊髓阿片镇痛环路的机理研究
Author: 王丽花
Degree Level: 博士
Issued Date: 2007-01-08
Degree Grantor: 中国科学院上海生命科学研究院
Place of Degree Grantor: 上海生命科学研究院
Supervisor: 张旭
Keyword: 电刺激 ; δ-阿片受体 ; 镇痛 ; 囊泡释放 ; 频率依赖 ; 胞内钙模式
Alternative Title: Study on mechanisms of peripheral electrical stimulation-modulated spinal sensory circuits for opioid analgesia
Major: 神经生物学
Abstract: 吗啡等m-阿片受体激动剂可以诱导强效的镇痛作用,但也伴随着较多的副作用,因而d-阿片受体(DOR)被认为是潜在的重要的镇痛药物靶点。然而在正常生理状态下DOR的激动剂只能诱导较小的镇痛作用,我们的研究表明外周电刺激大大增强了DOR介导的镇痛作用。在本研究中我们发现,在小鼠背根神经节小神经元中,只有少量的DOR位于细胞膜上,而大量的受体主要定位于大致密芯囊泡的泡膜上,并储存在胞浆内。电刺激可频率依赖性地增加背根节小细胞或C传入纤维末梢膜上的DOR的总量。用能够激活C纤维但不引起疼痛的外周神经电刺激可以大大增强鞘内注射DOR激动剂引起的镇痛效果。这种电刺激增强的DOR介导的脊髓镇痛作用具有电刺激强度和频率依赖性。用电流强度为0.26 mA 左右的10 Hz 电刺激可以大大提高胞膜DOR的表达,增强DOR介导的脊髓镇痛作用,且这种增强机制在急性痛和慢性痛条件下都有效。这些结果不但证明电刺激诱导表达在C纤维末梢膜表面的DOR可介导强效的镇痛作用,而且表明外周电刺激与DOR激动剂联合使用可能是一种新的镇痛策略。 进一步的细胞学机制研究发现,不同频率的电刺激引起胞内钙以不同模式升高,这些不同模式的胞内钙升高激活了肌球蛋白依赖的囊泡转运和/或破坏细胞表层的F-actin栅栏结构,这两个作用分别或协同帮助囊泡运输和释放,从而促使大量的大致密芯囊泡释放及DOR插入细胞膜。这些结果揭示了胞内钙模式依赖的大致密芯囊泡释放和受体上膜的一种新的细胞学机制。
English Abstract: δ-opioid receptor (DOR) is considered to be a target for developing pain therapies with less adverse effects. However, DOR agonists have been found to induce only weak or moderate antinociceptive effects. We here show that in dorsal root ganglion (DRG) small neurons and afferent C-fiber terminals, DORs are mainly associated with large dense-core vesicles (LDCVs) in the cytoplasma. Electrical stimulation (at 2-100 Hz) evoked a frequency-dependent membrane insertion of LDCV-associated DORs. A potent non-painful C-fiber-activated peripheral electrical stimulation (ES) largely potentiates intrathecal injection of DOR agonist-induced analgesia in both acute and chronic pain conditions. The ES-potentiated DOR-mediated spinal analgesia is dependent on the intensities and frequencies of stimuli. ES at about 0.26 mA at 10 Hz for 5 min is found to enhance surface expression of DORs and greatly elevated analgesic effect of DOR agonists. Thus, facilitation of DOR-mediated analgesia by preconditioning C-fibers with a brief electrical stimulation is a potential strategy for pain control. Further studies on the mechanism show that electrical stimuli induce frequency-dependent [Ca2+]i-patterns, which facilitate myosin-dependent LDCV translocation and/or disrupt cortical barrier F-actin to allow LDCV access to the cell surface. The two celluar processes synergistically contribute to [Ca2+]i-induced LDCV exocytosis and DOR insertion. This indicates a novel mechanism underlying the [Ca2+]i-pattern dependent LDCV exocytosis and DOR insertion in small DRG neurons.
Language: 中文
Content Type: 学位论文
URI: http://ir.sibs.ac.cn/handle/331001/2402
Appears in Collections:神经所(总)_学位论文

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Recommended Citation:
外周电刺激调制脊髓阿片镇痛环路的机理研究.王丽花[d].中国科学院上海生命科学研究院,2007.20-25
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