右美托咪定通过脊髓MrgC受体参与调控小鼠骨癌痛吗啡耐受  

Dexmedetomidine is involved in the regulation of morphine tolerance in mice with bone cancer through spinal MrgC receptor

作　　者：易珍 倪云成[2] 胡霞 唐轶珣 刘际童[1] 张宇[1] 黄晓玲[1] YI Zhen;NI Yun-cheng;HU Xia;TANG Yi-xun;LIU Ji-tong;ZHANG Yu;HUANG Xiao-ling(Department of Anesthesiology,Hunan Provincial People's Hospital,The First Affiliated Hospital of Hunan Normal University,Changsha 410005,China;Department of Anesthesiology,Third Xiangya Hospital of Central South University,Changsha 410005,China)

机构地区：[1]湖南省人民医院湖南师范大学附属第一医院麻醉科,长沙410005 [2]中南大学湘雅三医院麻醉科,长沙410005

出　　处：《中国疼痛医学杂志》2024年第10期742-749,共8页Chinese Journal of Pain Medicine

基　　金：国家自然科学基金青年科学基金(82101316);湖南省卫生健康委员会项目(20200708)。

摘　　要：目的:通过骨癌痛(bone cancer pain,BCP)小鼠模型明确右美托咪定是否参与吗啡耐受并探索其机制。方法:使用Lewis肺癌细胞系制备C57BL/6小鼠股骨癌痛动物模型。对BCP小鼠进行鞘内置管,连续7天注射吗啡诱导耐受产生。von Frey纤维丝评估小鼠左后足50%机械刺激缩足反射阈值(mechanical withdrawal threshold,MWT)、热板法评估热缩足潜伏期阈值(thermal withdrawal threshold,TWL)。给药第7天后取L3~L5节段脊髓,使用免疫组化实验和Western Blotting(WB)方法检测小鼠脊髓Mas相关基因C受体(Mas-related gene C receptor,MrgC)的表达。通过对吗啡耐受的BCP小鼠鞘内注射右美托咪定,探索其可能的机制。结果:自建模后第7天起,BCP小鼠左后足50%MWT显著下降,TWL明显缩短(P<0.05)。建模后第14天起鞘内给予吗啡,给药的第1~4天,BCP小鼠左后足50%MWT明显上升,TWL明显增加(P<0.05),给药的第5天开始50%MWT逐渐下降,TWL明显缩短。但预先鞘内给予右美托咪定后,给药的第1~7天BCP小鼠左后足50%MWT持续增高,TWL持续延长(P<0.05),且免疫组化和WB结果显示MrgC表达明显增加。结论:右美托咪定可缓解BCP小鼠吗啡耐受的形成,这一作用可能与右美托咪定促进BCP小鼠脊髓MrgC表达和活化有关。Objective:To investigate whether dexmedetomidine is involved in morphine tolerance and to explore the mechanism in a mouse model of bone cancer pain(BCP).Methods:An animal model of femoral bone cancer pain in C57BL/6 mice was prepared using Lewis lung cancer cell line.Bone cancer pain mice were intrathecally catheterized and morphine was injected for 7 consecutive days to induce the development of tolerance.The 50%mechanical withdrawal threshold(MWT)and the thermal withdrawal threshold(TWL)of the left hind-foot were assessed by von Frey fiber and hot plate test.After the 7th day of administration of morphine,the L3-L5 spinal cord segments was taken in mice.The expression of Mas-related gene C receptor(MrgC)in the spinal cord was detected by immunohistochemistry and Western Blotting(WB).Possible mechanisms were explored by intrathecal injection of dexmedetomidine in morphine-tolerant mice with bone cancer pain.Results:From day 7 after modeling,BCP mice showed a significant decrease in 50%MWT and a significant shortening of TWL.With intrathecal administration of morphine from day 14 after BCP modeling,50%MWT of the left hindfoot and TWL increased significantly from day 1 to day 4 after morphine administration,and 50%MWT gradually decreased and TWL shortened significantly from day 5 of morphine administration.However,after pretreatment of dexmedetomidine,BCP mice had a sustained increase in 50%MWT and a sustained prolongation of TWL from day 1 to day 7 of morphine administration,and immunohistochemistry and WB results showed a significant increase of MrgC expression.Conclusion:Dexmedetomidine attenuates the development of morphine tolerance in mice with bone cancer pain,which may be related to its promotion and activation of MrgC in the spinal cord of mice with bone cancer pain.

关 键 词：骨癌痛 吗啡耐受 MrgC受体 小鼠 右美托咪定 

分 类 号：R614[医药卫生—麻醉学]