川芎嗪通过抑制脊髓小胶质细胞活化缓解吗啡耐受
Tetramethylpyrazine attenuates morphine tolerance through suppressing spinal microglia activation in mice
-
摘要: 探讨川芎嗪对脊髓小胶质细胞活化和慢性吗啡耐受的影响并考察其作用机制。运用水浴甩尾法检测慢性吗啡耐受小鼠甩尾痛阈；免疫荧光法检测小鼠脊髓水平小胶质细胞标记分子(ionized calcium binding adapter molecule 1，IBA1)的变化情况；Western blot法检测p38 MAPK(mitogen-activated protein kinase，MAPK)磷酸化水平的改变，以及RT-PCR法检测川芎嗪对慢性吗啡耐受过程中白细胞介素-1β(IL-1β)和肿瘤坏死因子-α(TNF-α)mRNA表达水平的影响。实验结果发现，川芎嗪(15，30，60 mg/kg)能够剂量依赖性地抑制吗啡引起的脊髓IBA-1、p-p38 MAPK、p38、TNF-α和IL-1β水平的升高，改善慢性吗啡耐受。研究结果表明，川芎嗪能显著改善慢性吗啡耐受，其机制可能与抑制小胶质细胞p38 MAPK信号通路有关。Abstract: The aim of the present study was to investigate the effects and possible mechanism of tetramethylpyrazine(TMP)on morphine-induced microglia activation and tolerance. The antinociception and morphine tolerance were assessed in mice using hot-water tail flick test. IBA-1(ionized calcium binding adapter molecule 1), the marker of microglia, was detected by immumofluorescence method. The expression of p-p38 MAPK and total p38 MAPK(mitogen-activated protein kinase, MAPK)was analyzed by Western blot; real-time polymerase chain reaction(RT-PCR)was used to detect the expression level of tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β). Results showed that TMP(15, 30, 60 mg/kg, ip)inhibited morphine-induced up-regulation of IBA-1, p-p38, TNF-α and IL-1β in a dose-dependent manner, yet with no effect on the expression of total p38 MAPK. In conclusion, TMP significantly inhibited the activation of microglia evoked by morphine via p38 MAPK signaling pathway, thus attenuating morphine antinociception tolerance.
-
Keywords:
- tetramethylpyrazine /
- morphine /
- chronic tolerance /
- microglia
-
-
[1] Hutchinson MR,Northcutt AL,Chao LW,et al.Minocycline suppresses morphine-induced respiratory depression,suppresses morphine-induced reward,and enhances systemic morphine-induced analgesia[J].Brain Behav Immun,2008,22(8):1248-1256. [2] Horvath RJ, Romero-Sandoval EA, De Leo JA. Inhibition of microglial P2X4 receptors attenuates morphine tolerance,Iba1,GFAP and mu opioid receptor protein expression while enhancing perivascular microglial ED[J].Pain,2010,150(3):401-413. [3] Johnston IN, Milligan ED, Wieseler-Frank J, et al. A role for proinflammatory cytokines and fractalkine in analgesia,tolerance,and subsequent pain facilitation induced by chronic intrathecal morphine[J].J Neurosci,2004,24(33):7353-7365. [4] Zhou D,Chen ML,Zhang YQ,et al.Involvement of spinal microglial P2X7 receptor in generation of tolerance to morphine analgesia in rats[J].J Neurosci,2010,30(23): 8042-8047. [5] Wang X,Loram LC,Ramos K,et al.Morphine activates neuroinflammation in a manner parallel to endotoxin[J].Proc Natl Acad Sci U S A,2012,109(16):6325-6330. [6] Cui Y,Chen Y,Zhi JL,et al.Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance[J].Brain Res,2006,1069(1):235-243. [7] Wang Z,Ma W,Chabot JG,et al.Cell-type specific activation of p38 and ERK mediates calcitonin gene-related peptide involvement in tolerance to morphine-induced analgesia[J].FASEB J,2009,23(8): 2576-2586. [8] Hutchinson MR,Coats BD,Lewis SS,et al.Proinflammatory cytokines oppose opioid-induced acute and chronic analgesia[J].Brain Behav Immun,2008,22(8):1178-1189. [9] Ferrini F, Trang T, Mattioli TA, et al. Morphine hyperalgesia gated through microglia-mediated disruption of neuronal Cl(-)homeostasis[J].Nat Neurosci,2013,16(2): 183-192. [10] Berta T,Liu T,Liu YC,et al.Acute morphine activates satellite glial cells and up-regulates IL-1beta in dorsal root ganglia in mice via matrix metalloprotease-9[J].Mol Pain,2012,8:18. [11] Ji RR,Xu ZZ,Gao YJ.Emerging targets in neuroinflammation-driven chronic pain[J].Nat Rev Drug Discov,2014,13(7): 533-548. [12] Liang SD,Xu CS,Zhou T,et al.Tetramethylpyrazine inhibits ATP-activated currents in rat dorsal root ganglion neurons[J].Brain Res,2005,1040(1/2):92-97. [13] Hutchinson MR,Shavit Y,Grace PM,et al.Exploring the neuroimmunopharmacology of opioids:an integrative review of mechanisms of central immune signaling and their implications for opioid analgesia[J].Pharmacol Rev,2011,63(3):772-810. [14] Kawasaki,Zhang Y,Cheng JK,et al.Cytokine mechanisms of central sensitization:distinct and overlapping role of interleukin-1beta,interleukin-6,and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord[J].J Neurosci,2008,28(20):5189-5194. [15] Benarroch EE.Central neuron-glia interactions and neuropathic pain:overview of recent concepts and clinical implications[J].Neurology,2010,75(3):273-278. [16] Ji RR.MAP kinase and pain[J].Brain Res Rev,2009,60(1):135-148. [17] Chen Y,Geis C Sommer.The role of mitogen-activated protein kinase(MAPK)in morphine tolerance and dependence[J].Mol Neurobiol,2009,40(2):101-107. [18] Chen Y,Geis C Sommer.Activation of TRPV1 contributes to morphine tolerance:involvement of the mitogen-activated protein kinase signaling pathway[J].J Neurosci,2008,28(22): 5836-5845. -
期刊类型引用(10)
1. 陈俊锟，崔晚香，卜庆，万佩里，姚励功，梁林富，郭跃伟. 短指软珊瑚Sinularia sp.的多骨架类型萜类成分和生物活性研究. 中草药. 2023(05): 1370-1376 . 
百度学术
2. 康华丽，刘俊玲. 非小细胞肺癌组织中THRSP、ACACA的表达及其与临床预后的关系. 实用癌症杂志. 2023(12): 1951-1955 . 百度学术
3. 吴建美，尉迟邈，尹幸念，钱毅春，樊树理. 马铃薯抗性淀粉对高脂血症大鼠肝脏组织固醇调节元件结合蛋白-1c及裂解激活蛋白以及乙酰辅酶A羧化酶1表达的影响. 环境与健康杂志. 2023(04): 305-309+377 . 百度学术
4. 杨青，孙子羽，满都拉，王佳，刘瑾，金晶晶，陈忠军. 响应面法优化重组谷氨酸棒杆菌G-BC产脂肪酸的培养条件. 中国油脂. 2022(07): 121-124+131 . 百度学术
5. 王登杰，王文娟，邹忠兰，张爱华. LXRα/SREBP-1c在砷致大鼠脂代谢紊乱中的作用. 中华地方病学杂志. 2022(07): 517-523 . 百度学术
6. 吴建民，王建发，武瑞. 瘤胃微生物在奶牛乳脂肪合成中的调节作用研究进展. 中国兽医学报. 2021(01): 181-185 . 百度学术
7. 杨青，孙子羽，满都拉，王佳，刘瑾，金晶晶，陈忠军. 异源表达乙酰辅酶A羧化酶对大肠杆菌产脂肪酸的影响. 食品研究与开发. 2021(23): 150-155 . 百度学术
8. 邢海亮，董训赞，韩本勇，耿树香，宁德鲁，马婷，余旭亚. 二氧化碳联合核桃壳提取液促进单针藻Monoraphidium sp.QLZ-3的生长和油脂积累. 化工进展. 2020(04): 1575-1582 . 百度学术
9. 李硕熙，袁星星，杨磊，李丹丹，王炳予. 基于网络药理学方法分析芪参汤治疗非酒精性脂肪性肝病的作用机制及实验验证. 海南医学院学报. 2020(14): 1074-1082 . 百度学术
10. 崔佳丽，游金坤，李洁实，乔腾生，董训赞. 核桃壳提取液用于单针藻Monoraphidium sp. QLZ-3培养产油脂. 微生物学报. 2020(11): 2487-2497 . 百度学术
其他类型引用(12)
计量
- 文章访问数: 1107
- HTML全文浏览量: 0
- PDF下载量: 1863
- 被引次数: 22
下载:
