地卓西平对吗啡依赖大鼠部分脑区前脑啡肽基因表达的影响

The Effect of Dizocilpine on Levels of Proenkephalin mRNA in Defined Regions of Morphine Dependent Rats

目的:研究谷氨酸受体拮抗剂地卓西平对吗啡依赖大鼠部分脑区前脑啡肽(PENK)基因转录水平的影响。方法:18只雄性Sprague-Dawley大鼠随机等分吗啡组、干预组及对照组,每组6只。吗啡组大鼠腹腔注射吗啡,起始剂量5mg/kg,2次/d,逐日递增5mg,至第10天为50mg/kg;干预组大鼠每次注射吗啡前30分钟腹腔注射地卓西平0.075mg/kg;对照组按平行对照原则注射同体积的生理盐水。末次注射后3h取脑并冰冻切片,留取中脑腹侧被盖区(VTA)、伏隔核(NAc)、中脑导水管灰质(PAG)、杏仁核(AMG)、海马CA1区(HIPCA1)的切片。利用原位杂交及图像分析技术检测各脑区PENKmRNA的水平(吸光度A值)。结果:与对照组相比,吗啡组大鼠各脑区A值均明显降低,干预组大鼠在除AMG外的其它被检脑区也明显降低;与吗啡组相比,干预组大鼠VTA、NAc、AMG、HIPCA1区A值升高。结论:吗啡依赖大鼠多个脑区PENK基因表达明显下调,合并使用地卓西平可在一定程度上拮抗PENK基因表达的下调。

Objective: To investigate the effect of dizocilpine on levels of proenkephalin (PENK) mRNA in defined regions of morphine dependent rats. Methods: Eighteen male Sprague-Dawley rats were randomly assigned into morphine group (morphine was injected i.p. twice a day for 10 days in ascending dosage schedule, 5~50mg/kg), intervention group (dizocilpine was injected i.p. 30 min before the same morphine injection as morphine group), and control group (saline was injected i.p. according to the principle of control). Three hours after the last injections, the rat brains were removed and cut coronally. The sections containing ventral tegmental area (VTA), nucleus accumben (NAc), periaqueductal gray (PAG), amygdala (AMG) and hippocampus CA1 (HIPCA1) were selected and the mRNA levels of PENK were investigated by in situ hybridization. Results: Compared with control, the PENK mRNA levels significantly decreased in all defined areas of morphine-dependent rats, and decreased also in VTA, NAc, PAG, HIPCA1 of rats of intervention group. Compared with the morphine group, the PENK mRNA levels of rats of intervention group increased significantly in VTA, NAc, AMG, HIPCA1. Conclusions: Co-administration of dizocilpine with morphine might increase the gene expression of PENK inhibited by chronic morphine treatment and it might be one of the mechanisms of NMDA antagonists attenuating morphine tolerance and dependence.