Study Of Drug Dependence Of Morphine-6-glucuronic Acid Injection On Rat/mice And Its Genetic Toxicology Evaluation

Objective: Use morphine to induce drug dependence on rat/mice to evaluate the physical and psychic dependence after injecting morphine-6-glucuronic acid through behavioral experiment.And provide genetic testing reference for the clinical application through the genetic toxicity evaluation of injecting morphine-6-glucuronic acid.Method:1)Evaluate the physical dependence of M6 G injection through the precipitated withdrawal experiments on mice and replacement experiment on rats.2)Evaluate the psychic dependence of M6 G injection through the conditioned place preference experiment on rat.3)Evaluate whether M6 G injection has teratogenic and mutagenic effects or not through micronucleus tests in mice’s bodies,in vitro AMES experiments and in vitro chromosome aberration of Chinese hamster lung fibroblast.Results:1)ICR mice can be induced physical dependence by increasing dose of morphine hydrochloride and M6 G injection three times a day in the condition of total dose 1030 mg/kg in 7 days;the increasing dose of morphine for 3 times a day and constantly 6 days can induce SD rats obvious physical dependence.Withdrawal symptoms were relieved when M6 G was replaced.2)10 mg/kg morphine hydrochloride injection and 2.5~10 mg/kg M6 G injection can both induce psychic dependence on SD rats.3)M6G injection did not induce the genotoxic effect of bone marrow micronucleus on the mice.M6 G injection at the 50 ~ 5000 μg/dish dose had no mutagenicity on Salmonella typhimurium.M6 G injection could act for 4 hours in the metabolic conditions and for 4-24 hours in the non-metabolic activation conditions.In the condition that dose was less than or equal to 500 μg/mL,it had no teratogenesis effect on the lung fibroblasts of Chinese hamsters.Conclusions:1)M6G injection can lead to physical dependence,which is more obvious than the equivalent dose of morphine hydrochloride injection.2)M6G injection can lead to psychic dependence,which has no significant difference with the equivalent dose of morphine hydrochloride injection.3)M6G injection has no genetic toxicity.