大鼠丙泊酚精神依赖形成的机制:腺苷A2A受体-神经递质-ERK通路  

Mechanism of mental dependence of propofol in rats:adenosine A2A receptor-neurotransmitter-ERK pathway

作　　者：陈鹏丽 何毕晨 闫睿[2] 黄蓉 周涵丹 张冰[2] Chen Pengli;He Bichen;Yan Rui;Huang Rong;Zhou Handan;Zhang Bing(Third Clinical Medical College of Xinjiang Medical University,Urumqi 830000,China;Department of Anesthesiology,Affiliated Cancer Hospital of Xinjiang Medical University,Urumqi 830000,China)

机构地区：[1]新疆医科大学第三临床医学院,乌鲁木齐830000 [2]新疆医科大学附属肿瘤医院麻醉科,乌鲁木齐830000

出　　处：《中华麻醉学杂志》2021年第9期1092-1096,共5页Chinese Journal of Anesthesiology

基　　金：自治区自然科学基金计划基金项目(2018D01C259)。

摘　　要：目的探讨大鼠丙泊酚精神依赖形成的机制与腺苷A2A受体-神经递质-细胞外信号调节激酶(ERK)通路的关系。方法健康雄性SD大鼠48只,采用间断腹腔注射丙泊酚40 mg/kg,连续14 d的方法建立丙泊酚依赖模型。采用随机数字表法将大鼠分为6组(n=8):中枢对照组(c-C组)、中枢激动剂组(c-CGS组)、中枢拮抗剂组(c-DMPX组)、外周对照组(p-C组)、外周激动剂组(p-CGS组)和外周拮抗剂组(p-DMPX组)。c-CGS组和c-C组于建模后立即颅内注射腺苷A2A激动剂CGS-216802.5 ng/0.5μl或等量生理盐水,p-CGS组和p-C组腹腔注射CGS-216800.1 mg/kg或等量生理盐水;c-DMPX组于每次丙泊酚注射前20 min颅内注射腺苷A2A受体拮抗剂DMPX 50 ng/0.5μl,p-DMPX组腹腔注射DMPX 0.25 mg/kg。分别于建模前、建模后即刻、激动剂或生理盐水给药后(干预后)测定位置偏爱值(CPP值)。建模后1 d时处死大鼠取血标本及脑组织,采用ELISA法检测血浆及海马多巴胺(DA)、谷氨酸(Glu)及大脑皮层5-羟色胺(5-HT)水平,采用Western blot法检测大脑皮层磷酸化ERK1/2(p-ERK1/2)的表达。结果与建模前比较,建模后即刻c-C组、c-CGS组、p-C组和p-CGS组CPP值升高(P<0.05),c-DMPX组和p-DMPX组CPP值差异无统计学意义(P>0.05);与造模后即刻比较,干预后c-C组和p-C组CPP值差异无统计学意义(P>0.05),c-CGS组和p-CGS组CPP值升高(P<0.05)。与c-C组比较,c-CGS组海马DA和Glu含量增加,c-DMPX组海马Glu含量减少,大脑皮层5-HT含量增加,p-ERK1/2表达下调(P<0.05);与p-C组比较,p-CGS组血浆及海马DA和Glu、大脑皮层5-HT和p-ERK1/2水平差异无统计学意义(P>0.05),p-DMPX组海马DA和Glu含量减少,大脑皮层5-HT含量增加,p-ERK1/2表达下调(P<0.05)。结论大鼠丙泊酚精神依赖形成的机制可能与激活腺苷A2A受体,增加脑内兴奋性神经递质,进而上调ERK活性有关。Objective To investigate the relationship between the mechanism of mental dependence of propofol and adenosine A2A receptor-neurotransmitter-extracellular signal-regulated kinase(ERK)pathway in rats.Methods Forty-eight healthy male Sprague-Dawley rats,aged about 7 weeks,weighing 200-300 g,were used in this study.The model of propofol dependence was established by intraperitoneal injection of propofol 40 mg/kg for 14 consecutive days.The rats were divided into 6 groups(n=8 each)using a random number table method:central control group(group c-C),central agonist group(group c-CGS),central antagonist group(group c-DMPX),peripheral control group(group p-C),peripheral agonist group(group p-CGS)and peripheral antagonist group(group p-DMPX).Adenosine A2A agonist CGS-216802.5 ng/0.5μl was intracranially injected immediately after establishing the model in group c-CGS,while the equal volume of normal saline was given instead in c-C group.CGS-216800.1 mg/kg was intraperitoneally injected in group p-CGS,while the equal volume of normal saline was given instead in group p-C.Adenosine A2A receptor antagonist DMPX 50 ng/0.5μl was intracranially injected at 20 min before each propofol injection in group c-DMPX,and DMPX 0.25 mg/kg was intraperitoneally injected in group p-DMPX.The position preference value(CPP value)was determined before establishing the model,immediately after establishing the model,and after administration of agonist or normal saline(after intervention).The animals were sacrificed at 1 day after establishing the model,and blood samples and brain tissues were obtained for determination of the levels of dopamine(DA)and glutamate(Glu)in plasma and hippocampus and content of serotonin(5-HT)in cerebral cortex(by enzyme-linked immunosorbent assay)and expression of phosphorylated ERK1/2(p-ERK1/2)in cerebral cortex(by Western blot).Results Compared with the baseline before establishing the model,CPP value was increased immediately after establishing the model in c-C,c-CGS,p-C and p-CGS groups(P<0.05),and no significa

关 键 词：二异丙酚 物质相关性障碍 受体 腺苷A2A 神经递质 MAP激酶信号系统 

分 类 号：R749.61[医药卫生—神经病学与精神病学]