Studies On The Antagonistic Effects Of Ginsenosides On Morphine Dependence And Their Structure-Efficacy Relationships

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.