Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance
Activation of p38 mitogen-activated protein kinase in spinal microglia mediates morphine antinociceptive tolerance
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DOI：
10.1016/j.brainres.2005.11.066
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发表时间：
2006-01-19
期刊：
影响因子：
2.9
通讯作者：
Chen, PX
中科院分区：
文献类型：
--
作者：
Cui, Y;Chen, Y;Chen, PX
令人信服的证据表明，脊髓胶质细胞被激活的慢性吗啡治疗和参与吗啡耐受的发展。然而，吗啡耐受中胶质细胞活化的机制仍不清楚。本研究探讨了脊髓p38丝裂原活化蛋白激酶（p38 MAPK）在慢性吗啡镇痛耐受形成中的作用。我们发现，鞘内注射吗啡（15 μ g），每天连续7天显着诱导磷酸-p38（p-p38）免疫反应细胞在脊髓中的数量增加与慢性生理盐水或急性吗啡治疗的大鼠相比。双重免疫荧光染色显示，p-p38免疫反应仅限于在激活的脊髓小胶质细胞，而不是在星形胶质细胞或神经元。在每次吗啡注射前30分钟，连续7天重复鞘内给予4-（4-氟苯基）-2-（4-甲磺酰基苯基）-5（4-吡啶基）-1H-咪唑（SB 203580）（10 μ g或2 μ g），一种特异性p38抑制剂，显著减弱了对吗啡镇痛的耐受性，通过甩尾试验评估。然而，SB 203580（10 μ g）的单次鞘内给药并没有拮抗已建立的吗啡镇痛耐受性。总之，这些结果表明，p38 MAPK在脊髓小胶质细胞的激活参与吗啡镇痛耐受的发展。SB 203580抑制脊髓p38 MAPK可减弱但不逆转吗啡镇痛耐受。本研究首次证明脊髓小胶质细胞p38的激活在吗啡镇痛耐受的形成中起重要作用。(c)2005 Elsevier B. V.保留所有权利。
Compelling evidence has suggested that spinal glial cells were activated by chronic morphine treatment and involved in the development of morphine tolerance. However, the mechanisms of glial activation were still largely unknown in morphine tolerance. In present study, we investigated the role of p38 mitogen-activated protein kinase (p38 MAPK) in the spinal cord in the development of chronic morphine antinociceptive tolerance. We found that intrathecal administration of morphine (15 mu g) daily for 7 consecutive days significantly induced an increase in number of phospho-p38 (p-p38) immunoreactive cells in the spinal cord compared with chronic saline or acute morphine treated rats. Double immunofluorescence staining revealed that p-p38 immunoreactivity was exclusively restricted in the activated spinal microglia, not in astrocytes or neurons. Repeated intrathecal administration of 4-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)-5(4-pyridyl)-1H-imidazole (SB203580) (10 mu g or 2 mu g), a specific p38 inhibitor, 30 min before each morphine injection for 7 consecutive days significantly attenuated tolerance to morphine analgesia assessed by tail flick test. However, a single intrathecal administration of SB203580 (10 mu g) did not antagonize the established tolerance to morphine analgesia. Taken together, these findings suggested that p38 MAPK activation in the spinal microglia was involved in the development of morphine antinociceptive tolerance. Inhibition of p38 MAPK by SB203580 in the spinal cord attenuated but not reversed the tolerance to morphine analgesia. The present study provides the first evidence that p38 activation in spinal microglia played an important role in the development of tolerance to morphine analgesia. (c) 2005 Elsevier B.V. All rights reserved.