两种吗啡依赖模型大鼠脑内单胺神经递质的变化以及青藤碱的调节作用

The changes of monoamine neurotransmitters in two rat models of morphine dependence and the effects of sinomenine on morphine dependence

目的探讨吗啡依赖大鼠催促戒断模型与条件性位置偏爱模型大鼠脑内单胺类递质的变化以及中药活性成分青藤碱对其的影响。方法采用剂量递增法复制吗啡依赖大鼠模型，经纳洛酮催促，引发躯体戒断症状。连续给予吗啡（5mg／kg，sc）6d，采用倾向性训练程序训练大鼠，建立大鼠条件性位置偏爱模型。两个模型分别给予青藤碱低、高两个剂量（30mg／kg，60mg／kg，im）治疗。下丘脑去甲肾上腺素（NE）、5-羟色胺（5-HT）和多巴胺（DA）含量采用荧光分光光度法测定。结果1．吗啡依赖大鼠经纳洛酮催促后，戒断评分值明显升高，同时伴有下丘脑NE和5-HT水平升高[分别为（7．07±1．41）μg/g脑组织和（1．15±0．35）μg/g脑组织]，与空白对照组Ⅰ[分别为（3．34±0．97）μg/g脑组织和（0．49±0．21）μg／g脑组织]比较，差异有显著性（P〈0．01）。大鼠脑内DA水平下降[（0．28±0．12）μg／g脑组织]，与空白对照组1[（0．39±0．14）μg/g脑组织]比较，差异有显著性（P〈0．05）。2．在吗啡诱导的大鼠条件性位置偏爱模型，大鼠脑内DA和5-HT水平升高[分别为（1．13±0．36）μg／g脑组织和（1．23±0．34）μg/g脑组织]，与空白对照组Ⅱ[分别为（0．43±0．11）μg/g脑组织和（0．47±0．18）μg／g脑组织]比较，差异有显著性（P〈0．01）。NE则无明显改变[（3．28±1．10）μg/g脑组织]，与空白对照组Ⅱ[（3．57±1．17）μg／g脑组织]比较，差异无显著性（P〉0．05）。青藤碱连续用药可显著抑制催促戒断症状和吗啡引起的位置偏爱的形成，对脑内单胺神经递质水平有明显的降低作用。结论吗啡依赖的形成和戒断与脑内单胺神经递质有密切关系，吗啡的躯体戒断症状与NE和5-HT升高的关，而位置偏爱效应主要与DA水平升高有关。青藤碱能抑制纳洛酮催促戒断症状，消除吗啡诱导的大鼠位置偏爱的形成，对脑组织单胺类神经递质水平的紊乱具有调节作用。

Objective To investigate the changes of monoamine neurotransmitters of the brain in two rat models of morphine dependence,and to explore the effects of sinomenine on morphine dependence. Methods A physical dependent rat model was established with morphine at a gradually increasing dosage and the withdrawal syndrome was scored after naloxone precipitation. The conditioned place preference （CPP） in rats induced by morphine was used to investigate psychic dependence in rats. Contents of norepinephrine （NE）, dopamine （DA） and serotonin （5-HT） in hypothalamus of rats were assayed with a fluorescent method. Results 1. In naloxone precipitated withdrawal test of in morphine-dependent rats, after morphine withdrawal, the rats presented marked withdrawal symptoms and signs, their withdrawal scores were significantly increased, and the levels of NE and 5-HT in hypothalamus of the rats were siguificanfly increased than the control group Ⅰ （7.07 ± 1. 406 μg/g wet tissue and 1.15± 0. 346 μg/g wet tissue ,respectively, P〈0.01 ） ,but the content of DA was markedly reduced than the control group Ⅰ （0.28 ± 0. 121 μg/g wet tissue, P 〈 0.05 ）. 2. In CPP model, morphine caused a marked place preference in rats and the levels of DA and 5-HT in hypothalamus were significantly increased than the control group Ⅱ （ 1.13 ±0. 359 μg/g wet tissue and 1.23 ±0.343 μg/g wet tissue,respectively, P〈0.01 ） ,but the content of NE was not significantly changed（3.28 ± 1. 098 μg/g wet tissue, P〉 0.05）. Sinomenine could significantly inhibit the withdrawal syndrome and development of CPP induced by morphine in rats, and could suppress the rising of monoamine neurotransmitters of the brain in two morphine dependent models in rats. Conclusion In the physical dependent model induced by morphine in rats, the rising of NE and 5-HT in the rat brain were significant, hut in CPP model induced by morphine in rats, the levels of DA in the rat brain were enhanced predominately. Sinomenine could inhibit the withdrawal syndrome and development of CPP in rats, and regulate and improve the function of mouoamine nerve system.