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| Evaluation the physical dependence of Xuanfei Zhisuo Mixture in rats with natural withdrawal model and mice with precinitated withdrawal model |
| SONG Yuehong1 CHEN Ying2▲ ZHANG Chenxi2 JIA Yanli2 DONG Futian1 HAN Gang2 DONG Yansheng2▲ SONG Minping1▲ |
1.Gansu Pu’an Pharmaceutical Co. Ltd., Gansu Province, Wuwei 733006, China;
2.SAFE Medical Technology Co. Ltd., Hebei Province, Langfang 065500, China |
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Abstract Objective To evaluate the physical dependence potential of Xuanfei Zhisuo Mixture in rats with natural withdrawal model and mice with precinitated withdrawal model. Methods Sixty SPF SD rats aged 5 to 7 week-old, male and female, weighing 160 to 230 g, were randomly divided into solvent control group, Morphine Hydrochloride group, low, medium and high dose Xuanfei Zhixu Mixture groups according to body weight, with 12 rats in each group. The solvent control group was orally gavage with pure water, the Morphine Hydrochloride group was subcutaneously injected with Morphine Hydrochloride injection, and the dose groups of Xuanfei Zhisuo Mixture were orally gavaged 0.732、1.83、3.66 mg/（kg·d） of Xuanfei Zhisuo Mixture, respectively, and were given continuously for 30 d, three times a day. Withdrawal score within 156 h after withdrawal and body weight change at 14 d after withdrawal were observed from the second day after last administration. Sixty SPF Balb/c mice aged 3 to 6 week-old, male and female, weighing 16 to 24 g, were randomly divided into solvent control group, Morphine Hydrochloride group, low, medium and high dose Xuanfei Zhisuo Mixture groups according to their body weight, with 12 mice in each group. The solvent control group was orally gavage with pure water, the Morphine Hydrochloride group was subcutaneously injected with Morphine Hydrochloride injection, and the dose groups of Xuanfei Zhisuo Mixture were orally gavaged 1.83, 4.575, 9.15 mg/（kg·d） of Xuanfei Zhisuo Mixture, respectively, and were given continuously for five days, three times a day. Mice in each group were intraperitoneally injected with 2 mg/kg Naloxone six hours after the last administration, and the jumping times and twisting times within 30 min as well as body weight changes before and one hour after withdrawal were observed. Results Natural withdrawal test in rats showed that: Compared with the solvent control group, the withdrawal score of Morphine Hydrochloride group was increased, the withdrawal score of low dose Xuanfei Zhisuo Mixture group was significantly increased at 12 and 18 h, and the withdrawal score of medium and high dose Xuanfei Zhisuo Mixture groups was significantly increased at 12, 18, 36, 66, 84, and 108 h, with statistical significance (P < 0.05); compared with solvent control group, body weight change in Morphine Hydrochloride group was significantly decreased from day 2 to day 7 (P < 0.05), but there was no significant difference between the two groups from day 8 to day 14 (P ＞ 0.05). There was no significant difference in body weight between low, medium and high dose Xuanfei Zhisuo Mixture groups and solvent control group on the 1st to 14th day of natural withdrawal (P ＞ 0.05). Mice precinitated withdrawal experiment showed that: compared with the solvent control group, the jumping times and twisting times of mice in Morphine Hydrochloride group were increased, and the body weight change was significantly decreased, with statistical significance (P < 0.05), compared with the solvent control group, there were no significant differences in jumping and twisting times and body weight of mice in low, medium and high dose Xuanfei Zhisuo Mixture groups (P ＞ 0.05). Conclusion Natural withdrawal reaction is observed in 0.732, 1.83, and 3.66 mg/（kg·d） dose of Xuanfei Zhisuo Mixture in rats, and the lowest addictive dose is 0.732 mg/（kg·d）. In mice precinitated withdrawal, Xuanfei Zhisuo Mixture dose groups of 1.83, 4.575, and 9.15 mg/（kg·d） show no obvious withdrawal reaction.
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