淫羊藿素联合吗啡对骨癌痛小鼠的镇痛效应研究  

Study on the analgesic effects of icaritin in combination withm orphine on bone cancer pain in mice

作　　者：杨雪伟 袁贤达 田越 孙琳琳 蔡捷[1] 孟坤 邢国刚[1] YANG Xuewei;YUAN Xianda;TIAN Yue;SUN Linlin;CAI Jie;MENG Kun;XING Guogang(Neuroscience Research Institute,Peking University,Department of Neurobiology,School of Basic Medical Sciences,Peking University Health Science Center,Key Laboratory for Neuroscience,Ministry of Education of China&National Health Commission of China,Beijing 100191,China;Beijing Shenogen Pharma Group Ltd.,Life Science Park Road,Changping District,Beijing 102206,China;Department of Endocrinology,Peking University First Hospital,Beijing 100034,China)

机构地区：[1]北京大学神经科学研究所,北京大学基础医学院神经生物学系,教育部/卫健委神经科学重点实验室,北京100191 [2]北京盛诺基医药科技股份有限公司,北京102206 [3]北京大学第一医院内分泌科,北京100034

出　　处：《中国疼痛医学杂志》2024年第1期28-37,共10页Chinese Journal of Pain Medicine

基　　金：国家自然科学基金(82371227,82171226,81974169,81671085);北京市自然科学基金(7222105);国家重点研发计划项目(2019YFC1712104);“北京大学医学部-英国伦敦国王学院联合医学研究所(JI)”联合研究项目(BMU2021KCL001)。

摘　　要：目的:探究淫羊藿素对骨癌痛(bone cancer pain,BCP)小鼠的镇痛效应,以及淫羊藿素与吗啡联合用药的镇痛效应;确定半效剂量淫羊藿素与吗啡联合用药,在达到吗啡最大镇痛效应时所减少的吗啡用量。方法:使用雄性C57BL/6J小鼠及路易斯(Lewis)肺癌细胞建立BCP小鼠模型。通过测定机械刺激缩足反射阈值(mechanical withdrawal threshold,MWT),冷刺激缩足潜伏期(paw withdrawal latency,PWL)以及自发抬足次数和抬足保护时间以评估小鼠疼痛敏感度。结果:自造模后第7~14天起,BCP小鼠左侧(荷瘤侧)后爪MWT和PWL明显降低,自发抬足次数和抬足保护时间明显上升,并持续存在(P<0.05)。造模后第7~14天给予淫羊藿素,自第10~14天起淫羊藿素明显增加BCP小鼠左侧后爪的MWT和PWL,并减少自发抬足次数和抬足保护时间,停药后效应持续至造模后第18天(即停药后第4天)(P<0.05)。应用2倍EC50剂量淫羊藿素(200 mg/kg)与吗啡联合用药可明显延长停药后镇痛效应,停药后镇痛效应持续至造模后第21天(即停药后第7天)(P<0.05)。应用半效剂量淫羊藿素(100 mg/kg)与吗啡联合用药,达到吗啡最佳镇痛效应时最多可减少60%吗啡用量。结论:淫羊藿素对BCP小鼠有明显的镇痛效应,当与吗啡联合用药时,不仅明显延长了停药后的镇痛效应,还能够减少高达60%的吗啡用量。Objective:This study aimed to investigate the analgesic effect of icaritin on bone cancer pain(BCP)in mice and the potential synergistic analgesic effect of icaritin and morphine.Additionally,we sought to determine the extent of morphine dose reduction when icaritin was administered at a half-effective dose in combination with morphine.Methods:We established a mouse model of BCP using male C57BL/6J mice and lewis lung carcinoma(LLC)cells.We assessed the pain threshold by measuring the mechanical withdrawal threshold(MWT)in response to mechanical stimulation,the paw withdrawal latency(PWL)in response to cold stimulation,the frequency of spontaneous flinches,and the time spent guarding.Results:Between th th the 7 and 14 days after modeling,BCP mice exhibited a significant decrease in MWT and PWL in the ipsilateral(tumor-bearing)hind paw,along with a significant increase in spontaneous flinches and time spent guarding th th th th(P<0.05).Icaritin was administered from the 7 to the 14 day after modeling.Starting from the 10 to the 14 day,icaritin significantly increased MWT and PWL in the ipsilateral hind paw of BCP model mice,while reduced the frequency of spontaneous flinches and the time spent guarding.These analgesic effects persisted until the 18th th day after surgery(i.e.,the 4 day after drug discontinuation)(P<0.05).When icaritin was administered at a dose of 2×EC50(200 mg/kg)in combination with morphine,it significantly prolonged the post-analgesic effects after st th drug discontinuation,with these effects lasting until the 21 day after surgery(i.e.,the 7 day after drug discontinuation)(P<0.05).Furthermore,when icaritin was administered at a half-effective dose(100 mg/kg)in combination with morphine,it reduced the required morphine dosage by up to 60%while maintaining the best analgesic effect achievable with morphine.Conclusion:Icaritin exhibits a significant analgesic effect on bone cancer pain in mice.When combined with morphine,icaritin not only prolongs post-analgesic effects after drug discontinuatio

关 键 词：骨癌痛 淫羊藿素 吗啡 镇痛效应 

分 类 号：R738.1[医药卫生—肿瘤]