The Studies Of Active Fraction Of Semen Ziziphi Spinosae On Morphine-induced Conditioned Place Preference In Mice

The development of addiction caused by opioids involves of physical dependence and psychological dependence. No effective drug occurs in the treatment of psychological dependence. To develop new effective drugs or therapy to treat psychological dependence is an urgent task. The rewarding properties of opioids are one of the main causes of psychological dependence to opioids. Conditioned place preference (CPP) test has been widely used to assess the rewarding properties of drugs with addiction liability (including opioids).The research of the pharmacodynamics shows that Semen Ziziphi Spinosae has the function of restraining nerve center. It is low toxicity, safe-using and has very distinctly officinal value. As the main active component of Semen Ziziphi Spinosae , Spinosin has the effects of sedation, hypnogenesis, analgesia, and anticonvulsant action on the central nervous system.Objective:To establish morphine-induced conditioned place preference model and observe the expression of this effect. To investigate the effect of the active fraction of SZS on morphine-induced conditioned place preference (CPP) in mice, set up preliminary identification of the active fraction of Semen Ziziphi Spinosae and study the possible mechanism of the action. Methods:1. Established morphine-induced conditioned place preference model, and then the active fraction of SZS was extracted, separated and screened out on the CPP model.2. Observed the effects of the active fraction of SZS on the development and the expression of morphine-induced CPP in mice. The self-dependence effect of the active fraction of SZS was also evaluated.3. The active fraction of SZS was set up identification by HPLC.5. Nitric oxide(NO)output in the brain was assessed by nitrate reductase method.Results:1. Morphine was able to induce significant place preference in mice, indicated by a significant increase in the CPP score (P < 0.01). Morphine (6mg/kg, sc) induced mice to obtain a significant CPP and the CPP model was reliable and stable.2. The acetoacetate and n-butanol extract of Semen ziziphi spinosae could attenuate the CPP effect.3. FLA (160 mg/kg, ip) was co-administrated with morphine everyday. The results showed that co-administrated with morphine, FLA reduced the CPP score(P < 0.01), indicating that FLA may have effect on the development of morphine induced CPP. FLA (80mg/kg and 160mg/kg, ip) was administrated 30 min before the CPP testing to observe the effect of FLA on the expression of morphine-induced CPP. There was no significant difference between the FLA paired group and the control group(P >0.05).The mice were treated with FLA (80mg/kg and 160mg/kg, ip) instead of morphine. There was no significant difference between the FLA paired group and the control group, indicating that FLA may not induce CPP.4. The major element of FLA was Spinosin identified by HPLC.5. FLA(160 mg/kg)could inhibit NO output in the brain of morphine-dependence mice(P<0.05). Conclusion:1. Morphine (6mg/kg, sc) induced mice to obtain a significant CPP and the CPP model was reliable and stable.2. The acetoacetate and n-butanol extract of Semen ziziphi spinosae show inhibitory effect on CPP.3. FLA may be the active fraction of Semen ziziphi spinosae that can antagonize the CPP effect induced by morphine. FLA could restrain the development of morphine-induced CPP in mice to a certain extent.4. It has no effect on the expression of morphine-induced CPP in mice and has no potential of psychic dependence.5. The major element of FLA was Spinosin.6. The mechanism of antagonism of FLA on morphine psychic dependence may be related to the decrease of NO level in the brain of morphine-dependence mice.7. FLA may be potentially useful in the treatment of opiate dependence.