Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing
Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing
复制标题
DOI：
10.1046/j.1471-4159.2003.01969.x
复制
发表时间：
2003-09-01
影响因子：
4.7
通讯作者：
Yaksh, TL
中科院分区：
文献类型：
--
作者：
Svensson, CI;Marsala, M;Yaksh, TL
我们检查了 p38 丝裂原激活蛋白激酶 (MAPK) 抑制剂在伤害感受模型中的作用，并将这种作用与 p38 MAPK 在脊髓中的定位和表达水平相关联。鞘内给予 P 物质或皮内注射福尔马林后，脊髓中磷酸化的 p38 MAPK 迅速增加。免疫细胞化学显示磷酸化的 p38 MAPK 免疫反应细胞主要存在于背角 I-IV 层中。对神经元、小胶质细胞、星形胶质细胞和少突胶质细胞的标记物进行双重染色意外地揭示了与小胶质细胞的共定位，但不与神经元或其他胶质细胞共定位。 p38 MAPK 抑制剂（SB20358 或 SD-282）预处理对急性热阈值没有影响。然而，它们减弱了几种与脊髓敏化相关的伤害性模型中的痛觉过敏，包括直接脊髓激活（鞘内 P 物质）和周围组织炎症（足底内福尔马林或角叉菜胶）。 p38 MAPK 抑制剂预处理可以阻断脊髓敏化，其表现为环加氧酶 2 表达增强和炎症诱导的 Fos 阳性神经元出现，但治疗后则不能阻断。综上所述，这些结果表明脊髓 p38 MAPK 参与炎症引起的疼痛，并且激活的脊髓小胶质细胞在脊髓伤害性处理中发挥直接作用。
We examined the effect of p38 mitogen-activated protein kinase (MAPK) inhibitors in models of nociception and correlated this effect with localization and expression levels of p38 MAPK in spinal cord. There was a rapid increase in phosphorylated p38 MAPK in spinal cord following intrathecal administration of substance P or intradermal injection of formalin. Immuncytochemisty revealed that phosphorylated p38 MAPK-immunoreactive cells were predominantly present in laminae I-IV of the dorsal horn. Double-staining with markers for neurons, microglia, astrocytes and oligodendrocytes unexpectedly revealed co-localization with microglia but not with neurons or other glia. Pretreatment with p38 MAPK inhibitors (SB20358 or SD-282) had no effect on acute thermal thresholds. However, they attenuated hyperalgesia in several nociceptive models associated with spinal sensitization including direct spinal activation (intrathecal substance P) and peripheral tissue inflammation (intraplantar formalin or carrageenan). Spinal sensitization, manifested by enhanced expression of cyclo-oxygenase-2 and inflammation-induced appearance of Fos-positive neurons, was blocked by pretreatment, but not post-treatment, with p38 MAPK inhibitors. Taken together, these results indicate that spinal p38 MAPK is involved in inflammation-induced pain and that activated spinal microglia play a direct role in spinal nociceptive processing.