γ-氨基丁酸能去抑制对脊髓细胞外信号调节激酶2的激动作用  

γ-Aminobutyratergic disinhibition-mediated activation of spinal extracellular signal-regulated kinases 2

作　　者：时蕾[1] 刘燕妮[1] 索占伟[1] 曹静[1] 李帅[1] 许英明[1] 胡晓东[1] 

机构地区：[1]兰州大学药学院分子药理研究所,甘肃兰州740000

出　　处：《中国药理学与毒理学杂志》2012年第3期294-298,共5页Chinese Journal of Pharmacology and Toxicology

基　　金：教育部"新世纪优秀人才支持计划"(NCET-08-0259);国家自然科学基金(30870837);国家自然科学基金(81072626);兰州大学中央高校基本科研业务费专项资金(Lzujbky-2010-138)~~

摘　　要：目的探讨脊髓γ-氨基丁酸(GABA)能去抑制对细胞外信号调节激酶1/2(ERK1/2)活性的影响及其与痛行为改变的关系。方法正常小鼠鞘内注射(ith)比扣扣灵碱(荷包牡丹碱,bicuculline)50 ng.g-1(5μl)模拟GABA能去抑制,左后足底sc给予弗氏完全佐剂制备炎性疼痛模型,小鼠ith给予GABAA受体激动剂地西泮0.5μg.g-1(5μl)或ERK1/2抑制剂PD-98059 0.25μg.g-1(5μl)后,测定ERK1/2活性和小鼠缩足阈值。结果与正常对照组的缩足阈值(1.24±0.07)g相比,正常小鼠ith给予比扣扣灵碱50 ng.g-1的缩足阈值显著降低〔(0.42±0.17)g,P<0.05〕,给予PD-98059 0.25μg.g-1后缩足阈值显著升高〔(1.29±0.37)g,P<0.05〕。与炎性疼痛模型组的缩足阈值(0.28±0.06)g相比,炎症小鼠ith给予地西泮0.5μg.g-1的缩足阈值显著升高〔(0.99±0.12)g,P<0.05〕,且给予PD-98059 0.25μg.g-1后缩足阈值也显著升高〔(0.97±0.17)g,P<0.05〕。Western免疫印迹结果显示,与正常对照组相比,比扣扣灵碱显著提高ERK2的磷酸化水平〔(152±24)%,P<0.05〕。并且弗氏完全佐剂也可提高小鼠脊髓ERK2的磷酸化水平〔(163±42)%,P<0.05〕,ith给予地西泮0.5μg.g-1,则显著降低CFA诱发的小鼠脊髓ERK2的磷酸化水平〔(91±34)%,P<0.05〕,同时地西泮和PD-98059有效缓解炎性疼痛症状。结论 GABA能去抑制对脊髓背角ERK2有激活作用,并与炎性疼痛的形成有关。OBJECTIVE To investigate the effect of γ-aminobutyratergic （GABAergic） disinhibition on the activity of extracellular signal-regulated kinases 1 and 2 （ ERK1/2 ） in the spinal dorsal horn and its correlation with nociceptive behavioral sensitization. METHODS GABAA receptor antagonist bicuculline （50 ng·g-1;5 μl） was intrathecally （ith） given in intact mice to mimic GABAergic disinhibition. Complete Freund＇s adjuvant （CFA） was intradermally injected to evoke inflammatory pain, followed by spinal application of GABAA receptor agonist diazepam （0.5 μg·g-1; 5 μl） or ERK1/2 inhibitor PD-98059 （0.25 μg·g ;5μl） to detect the alteration in ERK1/2 activity and the paw withdrawal threshold （PWT）. RESULTS Compared with PWT of normal control group （1.24±0.07 ）g, bicuculline 50 ng·g- 1 in intact mice significantly decreased to （0.42±0. 17）g （P 〈0.05）, which, however, could be reversed by PD-98059 0.25 μg·g-1 to （ 1.29±0. 37 ） g （ P 〈 0.05 ）. Diazepam 0.5 μg·g-1 or PD-98059 0.25 μg·g-1 dramatically en- hanced the PWT values of inflamed mice from （0.28 ±0.06） g to （0.99±0. 12）g and （0.97±0. 17）g （P 〈 0.05 ）, respectively. Compared with saline group, bicuculline specifically increased the phosphorylation level of ERK2 to （ 152±24 ） % （ P 〈 0.05 ）. CFA injection also enhanced ERK2 phosphorylation to （163±42）% （P 〈 0.05 ） in the spinal dorsal horn of mice, whereas ith GABAA receptor agonist diazepam depressed CFA-induced phosphorylation of ERK2 to （91 ± 34）% （P 〈0. 05）. Meanwhile, both diazepam and PD-98059 effectively alleviated inflammatory pain. CON- CLUSION Inhibitory GABAergie innervation controls the activation of ERK2 in the spinal dorsal horn, which may be involved in the formation of inflammatory pain.

关 键 词：受体 γ-氨基丁酸 炎性疼痛 细胞外信号调节激酶1/2 脊髓背角 

分 类 号：R96[医药卫生—药理学]