离子型谷氨酸受体拮抗剂MK-801和NBQX对胶原诱导型关节炎大鼠的镇痛作用  

Analgesic effects of ionotropic glutamate receptor antagonists MK-801 and NBQX on collagen-induced arthritis rats

作　　者：朱惠[1] 朱蓉[1] 邓肇达 封昱辰 沈海丽[1] ZHU Hui ZHU Rong DENG Zhao-da FENG Yu-chen SHEN Hai-li(Department of Rheumatology, Lanzhou University Second Hospital, Lanzhou 730000, Chin)

机构地区：[1]兰州大学第二医院风湿免疫科,兰州730000

出　　处：《北京大学学报（医学版）》2016年第6期977-981,共5页Journal of Peking University:Health Sciences

基　　金：甘肃省科技支撑计划基金(144FKCA060);甘肃省卫生行业科研计划管理项目(GWGL2014-50)资助~~

摘　　要：目的:在大鼠胶原诱导关节炎(collagen-induced arthritis,CIA)模型中,使用不同离子型谷氨酸受体拮抗剂,即N-甲基-D-天冬氨酸(N-methyl-D-asparticacid,NMDA)受体拮抗剂MK-801及非NMDA受体拮抗剂NBQX,通过阻断谷氨酸与相应受体结合而产生镇痛作用,进而研究两种拮抗剂在镇痛作用方面对大鼠行为的影响,以及对分子生物学指标产生的影响,即应用上述拮抗剂后大鼠血清及组织液中环氧化酶-2(cyclooxygenase-2,COX-2)和Janus激酶-3(Janus-activated kinase,Jak3)等表达的变化。方法:建立大鼠CIA模型,通过体内研究,向大鼠关节腔内注射不同离子型谷氨酸受体拮抗剂MK-801和NBQX,观察CIA大鼠行为和分子生物学指标的改变。行为评估内容包括大鼠的触痛及关节肿胀情况,触痛情况使用机械性缩足阈值(paw-withdrawal threshold,PWT)来评价,同时使用排水法测足容积来评估肿胀情况。分子生物学指标相关研究即由大鼠心脏采血,并取组织匀浆液,检测血清及组织液中在拮抗剂使用后COX-2和Jak3等表达的变化。结果:MK-801和NBQX在单独或联合使用时均能表现出镇痛作用(P<0.01),且镇痛作用持续时间均大于24 h,两种拮抗剂均在注射后4 h达到镇痛作用的峰值,且NBQX比MK-801镇痛作用更强(P<0.05);MK-801和NBQX在单独及联合使用时,均不能改变CIA大鼠的足跖肿胀(P>0.05);MK-801可降低CIA大鼠COX-2的表达(P<0.01),NBQX则未见此作用(P>0.05);MK-801和NBQX对CIA大鼠的Jak3表达增高均未见产生影响(P>0.05)。结论:MK-801及NBQX均可产生镇痛作用,且NBQX比MK-801表现更强,但两者对肿胀均未见效果;NMDA受体与COX-2炎症通路有一定的交叉作用,而对于Jak3尚不能发现其与离子型谷氨酸信号通路存在交叉作用。Objective： The ionotropic glutamate receptorantagonists include two types： MK-801,antagonist of N-methyl-D-asparticacid（ NMDA） receptor,and NBQX,antagonist of non-NMDA receptor. The above-mentioned ionotropic antagonists can block the glutamate and its corresponding receptor binding to produce analgesic effect. The objective of this research was to study two antagonists in analgesic effect on rat behavior,as well as to investigate the down-regulation and up-regulation of cyclooxygenase-2（ COX-2）and Janus-activated kinase（ Jak3） in collagen-induced arthritis（ CIA） rat serum and tissue fluid after the application of these antagonists,that is,the effect on molecular biology. Methods： This study used the ionotropic glutamate receptors as the target and established CIA rat model. Vivo studies were used to observe changes in behavior and molecular biology of the CIA rat. Behavioral assessment includedmechanical allodynia and joint swelling in the CIA rat,where themechanical allodynia was measured using the paw-withdrawal threshold（ PWT） with Von Frey filaments according to the ＂Up-Down＂method,and the drainage volume was used to assess joint swelling. Then the blood samples taken from the heart of the rat and the tissue homogenate were collected to detect the down-regulation and up-regulation of COX-2 and Jak3 in the serum and tissue fluid after the antagonists wereused. Results： Using MK-801,NBQX alone or using the combination of these two antagonists,these three methods all could alleviate pain（ P〈0. 01）.The analgesic effect lasted more than 24 h. Both antagonists reached the peak of analgesia at the end of 4hours post-injection. NBQX had stronger analgesic effect than MK-801（ P〈0. 05）. Whether alone or combined use of these two antagonists,could not change the CIA rats＇ swelling of the joint（ P〈0. 05）.MK-801 could decrease the expression of COX-2（ P〈0. 01）. At the same time,NBQX did not have this effect（ P〈0. 05）. Using MK-801,NBQX alone or combination o

关 键 词：关节炎 类风湿 谷氨酸 受体 炎症 疼痛 

分 类 号：R593[医药卫生—内科学]