人参皂苷类成分对吗啡依赖的拮抗作用及其构效关系分析
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摘要
毒品泛滥已经成为当今一个严重的社会问题。其成瘾性是其泛滥的重要原因。为了寻求和研制有效的戒毒药物，各方面都做了很多研究。大力挖掘我国丰富的中药资源，是我国医药工作者的责任。人参作为中药宝库中历史悠久的瑰宝，其药理作用很多。有文献报道，人参有抗吗啡成瘾性的作用。但目前这方面的研究大多局限于人参整体的作用而没有系统的具体分析其中的有效成份。
本文采用小鼠位置偏爱和反向耐受模型初步考察了人参皂苷Rd、Rb2、Re、Rg1和拟人参皂苷RT5、F11对吗啡造成的精神依赖性的作用。结果表明，吗啡可造成小鼠条件性位置偏爱和自主活动增加。六种皂苷成份单独使用都不引起位置偏爱，人参皂苷Rd、Rb2、Rg1和拟人参皂苷RT5、F11对吗啡引起的位置偏爱的形成有明显抑制作用，而人参皂苷Re无作用；人参皂苷Re对吗啡引起位置偏爱后小鼠的恢复有明显促进作用，而其他成分作用不明显。进一步用[~3H]DIP、[~(34)S]GTPγS结合实验和[~3H]cAMP含量测定实验检测15种人参皂苷单体对吗啡引起的阿片受体信号转导的影响，结果发现人参皂苷在抑制吗啡与阿片受体结合、对G蛋白激活以及对吗啡引起cAMP含量变化的影响具有一定的构效关系，人参皂苷对吗啡作用的影响可以通过影响吗啡与阿片受体结合的途径来实现，也有通过其他途径影响吗啡作用的可能。
兴奋性氨基酸系统是近几年成瘾机制研究的新热点，同时关于药物成瘾与学习记忆的相关性研究也日渐深入。谷氨酸作为一种兴奋性氨基酸及神经递质在脑内广泛存在，尤其是在海马等与学习记忆相关的脑区。我们的研究发现，吗啡能够降低小鼠海马细胞外谷氨酸的含量，且这种作用可以被阿片受体拮抗剂纳络酮所阻断。这一结果进一步证实了吗啡成瘾与谷氨酸系统的相关性。在SHSY-5Y神经母细胞瘤细胞系中，应用real time RT-PCR方法发现吗啡处理24小时能够降低μ阿片受体mRNA的表达，升高EAAT3 mRNA的表达，人参皂苷类成分中部分单体能够拮抗吗啡对这两种基因转录的影响，其中人参皂苷对吗啡引起的阿片受体mRNA的表达降低的拮抗作用可能与其对cAMP通路的调节有关。
以上结果提示，人参皂苷具有拮抗吗啡造成的精神依赖性的作用，其作用效果与结构有一定的相关性，人参皂苷对吗啡的拮抗作用不仅是通过阿片受体系统调节，还可以通过其他系统进行调节。对人参皂苷拮抗吗啡作用机理的研究还有待于进一步深入。
Ginseng has many kinds of pharmacological effects. Recent researches have shown that ginseng can inhibit some effects of morphine. The studies to date are mainly focus on the total saponin or a few ginsenosides. To further understand the mechanism of the actions of ginsenosides on morphine and the structure-efficacy relationships of these saponins, we investigated the effects of 15 ginsenosides on morphine-induced actions.Firstly, we used the locomotor and conditioned place preference (CPP) model to investigate the effects of 6 ginsenosides, ginsenoside-Rgl, -Rd, -Rb2, -Re, pseudoginsenoside-RT5 and -Fll, on morphine actions. The results showed that Re had a different effect on morphine compared with other ginsenosides, and it could attenuate the effect of other ginsenosides when mixed together. Secondly, we tested the effects of ginsenosides on morphine-induced signal transduction, including receptor binding, G protein activation and cAMP level. Among the 15 ginsenosides, we found that the glucose on the OH of the moieties and the structure of the 20-C connected alkyl are critical for the effects of ginseonsides on morphine actions. By using microdialysis coupled to HPLC-ECD method, we found that morphine could decrease the extracellular glutamate concentration. The real time RT-PCR experiment showed that morphine decreased p. opioid receptor mRNA but increased the EAAT3 mRNA levels. Some ginsenosides could inhibit these effects and the effects of ginsenosides on u opioid receptor mRNA may be through the regulation of cAMP pathway.These results suggest ginsenosides have markly antagonistic effects on morphine actions and there exist structure-efficay relationships. It is of great value to further study the mechanism of actions of ginsenosides on morphine.
本文采用小鼠位置偏爱和反向耐受模型初步考察了人参皂苷Rd、Rb2、Re、Rg1和拟人参皂苷RT5、F11对吗啡造成的精神依赖性的作用。结果表明，吗啡可造成小鼠条件性位置偏爱和自主活动增加。六种皂苷成份单独使用都不引起位置偏爱，人参皂苷Rd、Rb2、Rg1和拟人参皂苷RT5、F11对吗啡引起的位置偏爱的形成有明显抑制作用，而人参皂苷Re无作用；人参皂苷Re对吗啡引起位置偏爱后小鼠的恢复有明显促进作用，而其他成分作用不明显。进一步用[~3H]DIP、[~(34)S]GTPγS结合实验和[~3H]cAMP含量测定实验检测15种人参皂苷单体对吗啡引起的阿片受体信号转导的影响，结果发现人参皂苷在抑制吗啡与阿片受体结合、对G蛋白激活以及对吗啡引起cAMP含量变化的影响具有一定的构效关系，人参皂苷对吗啡作用的影响可以通过影响吗啡与阿片受体结合的途径来实现，也有通过其他途径影响吗啡作用的可能。
兴奋性氨基酸系统是近几年成瘾机制研究的新热点，同时关于药物成瘾与学习记忆的相关性研究也日渐深入。谷氨酸作为一种兴奋性氨基酸及神经递质在脑内广泛存在，尤其是在海马等与学习记忆相关的脑区。我们的研究发现，吗啡能够降低小鼠海马细胞外谷氨酸的含量，且这种作用可以被阿片受体拮抗剂纳络酮所阻断。这一结果进一步证实了吗啡成瘾与谷氨酸系统的相关性。在SHSY-5Y神经母细胞瘤细胞系中，应用real time RT-PCR方法发现吗啡处理24小时能够降低μ阿片受体mRNA的表达，升高EAAT3 mRNA的表达，人参皂苷类成分中部分单体能够拮抗吗啡对这两种基因转录的影响，其中人参皂苷对吗啡引起的阿片受体mRNA的表达降低的拮抗作用可能与其对cAMP通路的调节有关。
以上结果提示，人参皂苷具有拮抗吗啡造成的精神依赖性的作用，其作用效果与结构有一定的相关性，人参皂苷对吗啡的拮抗作用不仅是通过阿片受体系统调节，还可以通过其他系统进行调节。对人参皂苷拮抗吗啡作用机理的研究还有待于进一步深入。
Ginseng has many kinds of pharmacological effects. Recent researches have shown that ginseng can inhibit some effects of morphine. The studies to date are mainly focus on the total saponin or a few ginsenosides. To further understand the mechanism of the actions of ginsenosides on morphine and the structure-efficacy relationships of these saponins, we investigated the effects of 15 ginsenosides on morphine-induced actions.Firstly, we used the locomotor and conditioned place preference (CPP) model to investigate the effects of 6 ginsenosides, ginsenoside-Rgl, -Rd, -Rb2, -Re, pseudoginsenoside-RT5 and -Fll, on morphine actions. The results showed that Re had a different effect on morphine compared with other ginsenosides, and it could attenuate the effect of other ginsenosides when mixed together. Secondly, we tested the effects of ginsenosides on morphine-induced signal transduction, including receptor binding, G protein activation and cAMP level. Among the 15 ginsenosides, we found that the glucose on the OH of the moieties and the structure of the 20-C connected alkyl are critical for the effects of ginseonsides on morphine actions. By using microdialysis coupled to HPLC-ECD method, we found that morphine could decrease the extracellular glutamate concentration. The real time RT-PCR experiment showed that morphine decreased p. opioid receptor mRNA but increased the EAAT3 mRNA levels. Some ginsenosides could inhibit these effects and the effects of ginsenosides on u opioid receptor mRNA may be through the regulation of cAMP pathway.These results suggest ginsenosides have markly antagonistic effects on morphine actions and there exist structure-efficay relationships. It is of great value to further study the mechanism of actions of ginsenosides on morphine.
引文
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