β-血小板衍生生长因子信号通路在吗啡耐受机制中的作用  

Role of PDGFR-β signal pathway in morphine tolerance

作　　者：刘红军[1] 高献忠[1] 金毅[1] 李伟彦[1] 

机构地区：[1]南京军区南京总医院麻醉科,南京医学博士210002

出　　处：《医学研究生学报》2015年第2期149-152,共4页Journal of Medical Postgraduates

基　　金：南京军区南京总医院科研基金(2013029)

摘　　要：目的评价细胞外信号调节激酶(extracellular signal-regulated kinase,ERK)和CAMP反应元件结合蛋白(cyclic AMP response element binding protein,CREB)信号通路在β-血小板衍生生长因子(beta platelet-derived growth factor,PDGF)受体介导的大鼠吗啡耐受中的作用。方法 36只健康雄性SD大鼠按随机数字表法分为6组(n=6):对照组(等渗盐水20μL)、吗啡组(吗啡15μg)、吗啡+伊马替尼组(吗啡15μg+伊马替尼10μg)、吗啡+PDGF-BB组(吗啡15μg+PDGF-BB 10ng)、伊马替尼组(伊马替尼10μg)、PDGF-BB组(PDGF-BB 10 ng)。各组分别鞘内注射药物20μL,1次/d,连续7 d。于给药前1d测定热缩足潜伏期(paw withdrawal latency,PWL)基础值,给药后1、3、5、7 d鞘内注射30 min后测定PWL,计算最大镇痛效应百分比(maximal possible effect,MPE)。第8天,各组大鼠鞘内单独注射吗啡15μg 30 min后测定PWL,计算MPE,测定PWL后取L4-5脊髓,Western blot法测定ERK、p-ERK、CREB和p-CREB的表达水平。结果吗啡组给药后第5、7天MPE值分别为(52.90±8.20)%和(15.1±3.80)%,较第1天[(100.00±0.00)%]明显降低(P<0.05);吗啡+PDGF-BB组给药后第5、7天MPE值分别为(43.51±5.42)%和(14.81±3.60)%,较第1天[(100.00±0.00)%]明显降低(P<0.05);而吗啡+伊马替尼组给药后第1、3、5、7天MPE值无明显变化;第8天单独鞘内注射15μg吗啡后,吗啡组、吗啡+PDGF-BB组和PDGFBB组MPE值分别为(16.22±2.51)%、(15.22±3.50)%(35.21±4.51)%,较对照组[(100.00±0.00)%]均明显降低(P<0.05);6组大鼠脊髓ERK和CREB表达水平差异无统计学意义;吗啡组、吗啡+PDGF-BB组和PDGF-BB组大鼠脊髓磷酸化ERK和磷酸化CREB表达较对照组均上调(P<0.05);吗啡+伊马替尼组大鼠脊髓磷酸化ERK和磷酸化CREB表达较吗啡组均下调(P<0.05)。结论 PDGFR-β信号通路在吗啡耐受过程中具有重要作用,具体机制与激活下游ERK和CREB通路有关。Objective Beta platelet-derived growth factor receptor（ PDGFR-β）-mediated signaling plays a key role in morphine tolerance,but its molecular mechanisms are not yet completely understood. The present study aims to investigate whether the extracellular signal-regulated kinase（ ERK） and cyclic AMP response element binding protein（ REB） signaling pathways are involved in the development of PDGFR-β activation-induced morphine tolerance in rats. Methods Thirty-six adult male SD rats were randomly divided into six groups of equal number： normal saline（ 20 μL）,morphine（ 15 μg）,morphine ＋ imatinib（ morphine 15 μg ＋ imatinib 10 μg）,morphine ＋ PDGF-BB（ morphine 15 μg ＋ PDGF-BB 10 ng）,imatinib（ 10 μg）,and PDGF-BB（ 10 ng）,all treated intrathecally at 20 μL once daily for 7 consecutive days. Paw withdrawal latency（ PWL） was measured 1 d before and 30 min after medication at 1,3,5,and 7 days,respectively,followed by calculation of the maximal possible effect of analgesia（ MPE）. On the8 th day,PWL was again obtained from all the rats at 30 min after intrathecal injection of morphine（ 15 μg）. Then,all the animals were sacrificed and the L4- 5 segment of the spinal cord was isolated for determination of the expressions of ERK, phosphorylated ERK（ p-ERK）,CREB,and phosphorylated CREB（ p-CREB） by Western blot. Results At 5 and 7 days after medication,MPE was significant decreased in the morphine group（ [52. 90 ± 8. 20] and[15. 12 ± 3. 80]%） and the morphine ＋ PDGF-BB group（ [43. 51 ± 5. 42]and[14. 81 ± 3. 60]%） as compared with（ 100. 00 ±0. 00） % in both groups at 1 day（ P〈0. 05）,but had no significant changes in the morphine ＋ imatinib group at 1,3,5,and 7days. After intrathecal injection of morphine on the 8th day,MPE was（ 16. 22 ± 2. 51） % in the morphine group,（ 15. 22 ± 3. 50） %in the morphine ＋ PDGF-BB group,and（ 35. 21 ± 4. 51） % in the PDGF-BB group,all remarkably lower than（ 100. 00 ± 0. 00） %in the co

关 键 词：细胞外信号调节激酶 CAMP反应元件结合蛋白 β-血小板衍生生长因子受体 药物耐受性 吗啡 

分 类 号：R363[医药卫生—病理学]