Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia
Intrathecal minocycline attenuates peripheral inflammation-induced hyperalgesia by inhibiting p38 MAPK in spinal microglia
复制标题
DOI：
10.1111/j.1460-9568.2005.04451.x
复制
发表时间：
2005-11-01
影响因子：
3.4
通讯作者：
Webb, M
中科院分区：
文献类型：
--
作者：
Hua, XY;Svensson, CI;Webb, M
脊髓小胶质细胞中p38丝裂原活化蛋白激酶(P38)的激活与脊髓伤害性反应有关。米诺环素是一种四环素衍生物，具有选择性地抑制小胶质细胞激活的作用，这一功能与其抗生素活性不同。在本研究中，我们观察了鞘内注射米诺环素(IT)对炎性痛敏实验模型的抗伤害性作用，以及米诺环素对刺激诱导的脊髓小胶质细胞p38激活的影响。鞘内注射米诺环素可剂量依赖性地减少福尔马林诱导的大鼠第二时相缩腿行为，并可预防角叉菜胶足部注射所致的热痛敏反应。相比之下，全身注射米诺环素(腹膜内)抑制了福尔马林诱导的第一阶段而不是第二阶段的退缩，对卡拉胶诱导的痛敏没有影响。米诺环素可完全阻断IT递送N-甲基-D-天冬氨酸所引起的中枢痛敏反应。用Western blotting和免疫组织化学方法检测，注射角叉菜胶后脊髓背侧p38(P-p38)的磷酸化(激活)增加。P-p38免疫反应增强主要见于小胶质细胞，但也见于一小部分神经元。米诺环素在阻断角叉菜胶致痛敏的IT剂量时，也减弱了小胶质细胞中增加的P-p38。此外，米诺环素抑制培养的脊髓小胶质细胞内毒素诱导的P-p38。综上所述，这些发现表明，给予米诺环素在组织损伤和炎症诱发的疼痛模型中产生了有效和一致的抗伤害性感受，并有力地支持了这种作用是通过直接抑制脊髓小胶质细胞和随后激活这些细胞中的p38来实现的。
Activation of p38 mitogen-activated protein kinase (p38) in spinal microglia is implicated in spinal nociceptive processing. Minocycline, a tetracycline derivative, displays selective inhibition of microglial activation, a function that is distinct from its antibiotic activity. In the present study we examined antinociceptive effects of intrathecal (IT) administration of minocycline in experimental models of inflammation-evoked hyperalgesia in addition to the effect of minocycline on stimulation-induced activation of p38 in spinal microglia. Intrathecal minocycline produced a dose-dependent reduction of formalin-evoked second-phase flinching behaviour in rats, and prevented thermal hyperalgesia induced by carrageenan injection into the paw. In contrast, systemic delivery (intraperitoneally) of minocycline inhibited the first but not the second phase of formalin-induced flinching, and it had no effect on carrageenan-induced hyperalgesia. Centrally mediated hyperalgesia induced by IT delivery of N-methyl-D-aspartate was completely blocked by IT minocycline. An increase in phosphorylation (activation) of p38 (P-p38) was observed in the dorsal spinal cord after carrageenan paw injection, assessed by both Western blotting and immunohistochemistry. The increased P-p38 immunoreactivity was seen primarily in microglia but also in a small population of neurons. Minocycline, at the IT dose that blocked carrageenan-induced hyperalgesia, also attenuated the increased P-p38 in microglia. In addition, minocycline suppressed lipopolysaccharide-evoked P-p38 in cultured spinal microglial cells. Taken together, these findings show that minocycline given IT produces a potent and consistent antinociception in models of tissue injury and inflammation-evoked pain, and they provide strong support for the idea that this effect is mediated by direct inhibition of spinal microglia and subsequent activation of p38 in these cells.