大鼠自然戒断和小鼠催促戒断模型评价宣肺止嗽合剂的躯体依赖作用

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摘要目的采用大鼠自然戒断和小鼠催促戒断模型评价宣肺止嗽合剂的躯体依赖性潜力。方法大鼠自然戒断试验选用60只SPF级5～7周龄的SD大鼠，雌雄各半，体重160～230 g，将其根据体重随机分为溶剂对照组，盐酸吗啡组，低、中、高剂量宣肺止嗽合剂组，每组12只。溶剂对照组经口灌胃纯水，盐酸吗啡组皮下注射盐酸吗啡注射液，宣肺止嗽合剂各剂量组分别经口灌胃0.732、1.83、3.66 mg/（kg·d）剂量的宣肺止嗽合剂，各组均连续给药30 d，3次/d。末次给药后次日起观察戒断后156 h内的戒断评分和戒断后14 d的体重变化。小鼠催促戒断试验选用60只SPF级3～6周龄的Balb/c小鼠，雌雄各半，体重16～24 g，将其根据体重随机分为溶剂对照组，盐酸吗啡组，低、中、高剂量宣肺止嗽合剂组，每组12只。溶剂对照组经口灌胃纯水，盐酸吗啡组皮下注射盐酸吗啡注射液，宣肺止嗽合剂各剂量组分别经口灌胃1.83、4.575、9.15 mg/（kg·d）剂量的宣肺止嗽合剂组制剂，各组均连续给药5 d，3次/d。末次给药后6 h内腹腔注射2 mg/kg纳洛酮并观察30 min内跳跃次数、扭体次数和戒断前与戒断后1 h的体重变化。结果大鼠自然戒断试验显示：与溶剂对照组比较，盐酸吗啡组戒断评分升高，宣肺止嗽合剂低剂量组在12、18 h的戒断评分显著升高，宣肺止嗽合剂中、高剂量组在12、18、36、66、84、108 h的戒断评分显著升高，差异有统计学意义（P ＜ 0.05）；与溶剂对照组比较，盐酸吗啡组体重变化在第2～7天显著降低（P ＜ 0.05），在第8～14天两组体重变化比较，差异无统计学意义（P ＞ 0.05）；低、中、高剂量宣肺止嗽合剂组在自然戒断第1～14天体重变化与溶剂对照组比较，差异无统计学意义（P ＞ 0.05）。小鼠催促戒断试验显示：与溶剂对照组比较，盐酸吗啡组小鼠跳跃次数、扭体次数升高，体重变化显著降低，差异有统计学意义（P ＜ 0.05），低、中、高剂量宣肺止嗽合剂组小鼠的跳跃、扭体次数和体重变化与溶剂对照组比较，差异无统计学意义（P ＞ 0.05）。结论大鼠自然戒断中0.732、1.83、3.66 mg/（kg·d）宣肺止嗽合剂均出现了轻微的戒断反应，最低成瘾剂量为0.732 mg/（kg·d）；小鼠催促戒断中，1.83、4.575、9.15 mg/（kg·d）宣肺止嗽合剂均未出现明显的戒断反应。

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	宋月红1 陈瑛2▲ 张晨熙2 贾艳丽2 董福天1 韩刚2 董延生2▲ 宋敏平1▲

关键词 ：宣肺止嗽合剂, 盐酸吗啡, 自然戒断, 催促戒断, 躯体依赖

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.

Key words： Xuanfei Zhixu Mixture Morphine Hydrochloride Natural withdrawal Precinitated withdrawal Physical dependence

基金资助:甘肃省科学技术厅“科技助力经济2020”重点专项项目。

通讯作者: ▲共同通讯作者

引用本文:

宋月红1 陈瑛2▲ 张晨熙2 贾艳丽2 董福天1 韩刚2 董延生2▲ 宋敏平1▲. 大鼠自然戒断和小鼠催促戒断模型评价宣肺止嗽合剂的躯体依赖作用[J]. 中国医药导报, 2022, 19(13): 33-37.
SONG Yuehong1 CHEN Ying2▲ ZHANG Chenxi2 JIA Yanli2 DONG Futian1 HAN Gang2 DONG Yansheng2▲ SONG Minping1▲. Evaluation the physical dependence of Xuanfei Zhisuo Mixture in rats with natural withdrawal model and mice with precinitated withdrawal model. 中国医药导报, 2022, 19(13): 33-37.

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