Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1β-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord
Inhibition of p38 mitogen-activated protein kinase attenuates interleukin-1β-induced thermal hyperalgesia and inducible nitric oxide synthase expression in the spinal cord
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DOI：
10.1111/j.1471-4159.2005.03226.x
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发表时间：
2005-08-01
影响因子：
4.7
通讯作者：
Wong, CS
中科院分区：
文献类型：
--
作者：
Sung, CS;Wen, ZH;Wong, CS
我们最近报道，鞘内（i.t.）注射100 ng的白细胞介素-1 β（IL-1 β）诱导大鼠脊髓中诱导性一氧化氮合酶（NOS）表达和一氧化氮（NO）产生，并导致热痛觉过敏。本研究进一步探讨了丝裂原活化蛋白激酶（MAPK）在i.t. IL-1 β介导的iNOS-NO级联在脊髓伤害性信号转导中的作用所有大鼠均植入i.t.导管，有或没有额外的微透析探针。对辐射热的缩爪潜伏期用于评估热痛觉过敏。免疫印迹法检测脊髓后角NOS和MAPK蛋白的表达。同时测定CSF透析液中的[NO]。鞘内IL-1 β导致在IL-1 β注射（i.t.）后30 - 240分钟脊髓中磷酸化p38（p-p38）MAPK蛋白表达的时间依赖性上调。然而，磷酸化的细胞外信号调节激酶（p-ERK）和磷酸化的c-Jun NH 2-末端激酶（p-JNK）均不受影响。注射IL-1 β后，p38、ERK和JNK MAPK蛋白的总量不受影响。选择性p38 MAPK、JNK或ERK抑制剂单独鞘内给药不影响脊髓中的热伤害性阈值或NOS蛋白表达。然而，用p38 MAPK抑制剂预处理显著降低IL-1 β诱导的p-p38 MAPK表达38- 49%，并且几乎完全阻断随后的NOS表达（降低86.6%）、NO产生和热痛觉过敏。相反，ERK和JNK抑制剂预处理仅部分（约50%）抑制IL-1 β诱导的脊髓NOS表达。我们的结果表明p38 MAPK在i.t. IL-1 β诱导的脊髓敏化和伤害性信号转导。
We have reported recently that intrathecal (i.t.) injection of interleukin-1 beta (IL-1 beta), at a dose of 100 ng, induces induciblenitric oxide synthase (NOS) expression and nitric oxide (NO) production in the spinal cord and results in thermal hyperalgesia in rats. This study further examines the role of mitogen-activated protein kinase (MAPK) in i.t. IL-1 beta-mediated iNOS-NO cascade in spinal nociceptive signal transduction. All rats were implanted with an i.t. catheter either with or without an additional microdialysis probe. Paw withdrawal latency to radiant heat is used to assess thermal hyperalgesia. The NOS and MAPK protein expression in the spinal cord dorsal horn were examined by western blot. The [NO] in CSF dialysates were also measured. Intrathecal IL-1 beta leads to a time-dependent up-regulation of phosphorylated p38 (p-p38) MAPK protein expression in the spinal cord 30240 min following IL-1 beta injection (i.t.). However, neither the phosphorylated extracellular signal-regulated kinase (p-ERK) nor phosphorylated c-Jun NH2-terminal kinase (p-JNK) was affected. The total amount of p38, ERK, and JNK MAPK proteins were not affected following IL-1 beta injection. Intrathecal administration of either selective p38 MAPK, or JNK, or ERK inhibitor alone did not affect the thermal nociceptive threshold or NOS protein expression in the spinal cord. However, pretreatment with a p38 MAPK inhibitor significantly reduced the IL-1 beta-induced p-p38 MAPK expression by 38-49%, and nearly completely blocked the subsequent NOS expression (reduction by 86.6%), NO production, and thermal hyperalgesia. In contrast, both ERK and JNK inhibitor pretreatments only partially (approximate to 50%) inhibited the IL-1 beta-induced NOS expression in the spinal cord. Our results suggest that p38 MAPK plays a pivotal role in i.t. IL-1 beta-induced spinal sensitization and nociceptive signal transduction.