药学学报, 2021, 56(7): 1921-1926
引用本文:
张欢, 王舒哲, 李贝贝, 王翊名, 刘小珍, 陈华英, 邱云良. 不同方法建立固定比率为10的大鼠吗啡药物辨别模型[J]. 药学学报, 2021, 56(7): 1921-1926.
ZHANG Huan, WANG Shu-zhe, LI Bei-bei, WANG Yi-ming, LIU Xiao-zhen, CHEN Hua-ying, QIU Yun-liang. Different methods establish a rat model of morphine drug discrimination with a fixed ratio 10[J]. Acta Pharmaceutica Sinica, 2021, 56(7): 1921-1926.

不同方法建立固定比率为10的大鼠吗啡药物辨别模型
张欢1,2, 王舒哲1,2, 李贝贝2, 王翊名3, 刘小珍2,4, 陈华英2, 邱云良2*
1. 上海工程技术大学化学化工学院, 上海 201620;
2. 中国医药工业研究总院, 上海益诺思生物技术股份有限公司, 上海 201203;
3. 上海健康医学院药学院, 上海 201318;
4. 复旦大学药学院, 上海 201203
摘要:
使用不同方法建立固定比率(fixed ratio,FR)为10(FR10)的大鼠吗啡药物辨别模型以探究何种方法可缩短建模时长并进行剂量反应关系测试和半数有效剂量(median effective dose,ED50)值测定。动物福利和实验过程均遵循上海益诺思生物技术股份有限公司动物伦理委员会的规定。40只大鼠进行食物训练,将食物训练成功的动物分为2组[组1(单杆+双杆训练)、组2(双杆训练)],每组均腹腔注射5.6 mg·kg-1的吗啡或生理盐水进行辨别训练,辨别训练成功的动物给予不同剂量的吗啡进行替代,探究辨别效应和剂量之间的关系,并计算ED50值。结果显示:食物训练阶段:有34只大鼠食物训练成功进入到辨别训练;辨别训练阶段:组1中首次满足辨别训练标准的动物共14只,约需(40.71±2.93)天,组2中首次满足辨别训练标准的动物共13只,约需(51.15±2.55)天,由此可见使用单杆+双杆训练的方法优于仅使用双杆训练,且与组1相比有统计学差异(P<0.05);替代测试阶段:共17只大鼠完成吗啡所有剂量的替代,不同剂量吗啡(0、0.1、0.5、1、3、5.6和10 mg·kg-1)替代所产生的伴吗啡杆反应百分数分别为(9.56±3.13)%、(9.01±5.83)%、(13.82±7.95)%、(29.04±10.13)%、(41.70±10.65)%、(85.36±7.16)%、(94.56±2.76)%,表明吗啡剂量在0~10 mg·kg-1之间诱导的辨别刺激效应呈剂量依赖性增加,产生很好的剂量反应曲线,通过线性拟合求得吗啡ED50值为4.74 mg·kg-1。上述结果表明,通过不同方法成功建立了FR10吗啡药物辨别模型,使用单杆+双杆训练的方法优于仅使用单杆训练且可相对缩短辨别训练周期。
关键词:    吗啡      药物辨别      依赖性      安全评价      药物滥用     
Different methods establish a rat model of morphine drug discrimination with a fixed ratio 10
ZHANG Huan1,2, WANG Shu-zhe1,2, LI Bei-bei2, WANG Yi-ming3, LIU Xiao-zhen2,4, CHEN Hua-ying2, QIU Yun-liang2*
1. College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai 201620, China;
2. Shanghai InnoStar Bio-Tech Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China;
3. School of Pharmacy, Shanghai University of Medicine and Health Sciences, Shanghai 201318, China;
4. School of Pharmacy, Fudan University, Shanghai 201203, China
Abstract:
In this study, a rat morphine drug discrimination model with a fixed ratio (FR) of 10 (FR10) was established using different methods to explore which methods can shorten the modeling time and test the dose-response relationship and median effective dose (ED50) value. Animal welfare and experimental procedures are in accordance with the provision of the Animal Ethics Committee of Shanghai InnoStar Bio-tech Co., Ltd. Forty rats were initially shaped to press lever under a fixed-ratio schedule of food reinforcement. The animals that were successfully trained under a FR10 schedule of food reinforcement were divided into two groups, namely the single-lever + double-lever training group 1 and the double-lever training group 2. In each group, rats were trained to discriminate morphine at 5.6 mg·kg-1 from saline by the intraperitoneal route. After training, different doses of morphine were used to substitute for training dose of morphine, the dose-response curve for morphine were identified in rats, and the ED50 value was calculated. The results showed that, in food training phase:34 rats successfully entered the discrimination training during food training; in discrimination training phase:14 animals in group 1 met the discrimination training standard for the first time, which took about (40.71±2.93) days, and there were 13 animals in group 2 that met the discrimination training criteria for the first time, and it took about (51.15±2.55) days. It can be seen that the method of single-lever + double-lever training is better than single-lever training, and the difference is significant compared with group 1 (P<0.05); in generalization test phase:there are 17 rats completed morphine generalization test, and the percentages of morphine-lever responses produced by the generalization test of different doses of morphine (0, 0.1, 0.5, 1, 3, 5.6, and 10 mg·kg-1) were (9.56±3.13)%, (9.01±5.83)%, (13.82±7.95)%, (29.04±10.13)%, (41.70±10.65)%, (85.36±7.16)%, (94.56±2.76)%, respectively. The results showed that the discriminative stimulative effect induced by morphine dose between 0-10 mg·kg-1 increased in a dose-dependent manner, producing a good dose-response curve, and the ED50 value of morphine was 4.74 mg·kg-1 by linear fitting. The above results showed that, the FR10 morphine drug discrimination model has been successfully established using different methods; the single-lever + double-lever training method is better than the single-lever training, and can relatively shorten the discrimination training cycle.
Key words:    morphine    drug discrimination    dependence    safety evaluation    drug abuse   
收稿日期: 2021-01-25
DOI: 10.16438/j.0513-4870.2021-0132
基金项目: 上海市科委研发共同服务平台(18DZ2290100).
通讯作者: 邱云良,Tel:86-21-60211999-3214,E-mail:ylqiu@ncdser.com
Email: ylqiu@ncdser.com
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