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cAMP 反应元件结合蛋白介导磷酸化细胞外信号调节激酶 在神经病理性痛形成中的作用

宋雪松¹, 徐艳冰², 曹君利^2,*, 何建华², 张励才², 曾因明²

¹吉林大学白求恩医学部第一临床学院麻醉科, 长春 130021；²江苏省麻醉医学研究所, 江苏省麻醉学重点实验室, 徐州 221002

摘要

采用行为学、免疫组织化学和 Western blot 方法，观察鞘内注射细胞外信号调节激酶(extracellular signal-regulate kinase, ERK)信号转导通路阻滞剂对慢性压迫性损伤(chronic constriction injury, CCI)大鼠痛行为及脊髓背角内磷酸化 cAMP 反应元件 结合蛋白(phosphorylated cAMP response-element binding protein, pCREB)和 Fos 表达变化的影响，探讨 ERK/CREB 转导通路 在神经病理性疼痛中的作用。结果表明，CCI 可明显增加双侧脊髓背角 pCREB、损伤侧脊髓背角浅层 Fos 阳性神经元表 达，以 CCI 后 3 与 5 d 时尤为显著。鞘内注射促分裂原活化蛋白激酶激酶(mitogen-activated protein kinase kinase, MEK)阻滞 剂 U0126 及 ERK 反义寡核苷酸在减轻大鼠痛行为的同时，能明显抑制双侧脊髓背角内 pCREB 的表达，同时，Fos 阳性神 经元的表达也明显减少。大鼠痛行为及脊髓背角 pCREB 和 Fos 的表达在时相上一致。上述结果提示 pCREB 参与 pERK 介 导的神经病理性疼痛。

关键词： cAMP 反应元件结合蛋白; 神经病理性痛; 原癌基因 c-fos; 细胞外信号调节激酶

cAMP response-element binding protein participates in the phosphorylated extracellular signal-regulate kinase mediated neuropathic pain

SONG Xue-Song¹, XU Yan-Bing², CAO Jun-Li^2,*, HE Jian-Hua², ZHANG Li-Cai², ZENG Yin-Ming²

¹Department of Anesthesiology, First Clinical College of N. Bethune Centre Health Sciences, Jilin University, Changchun 130021, China；² Jiangsu Institute of Anesthesiology, Jiangsu Key Laboratory of Anesthesiology, Xuzhou 221002, China

Abstract

It has been reported that extracellular signal-regulate kinase (ERK) is involved in the modulation of nociceptive information and central sensitization produced by intense noxious stimuli and/or peripheral tissue inflammation. Few studies have explored the relationship between ERK and cAMP response-element binding protein (CREB) in neuropathic pain after nerve injury, such as chronic constriction injury (CCI) of the sciatic nerve. In the present study, CCI model was employed to investigate the activation of ERK on the expression of phosphorylated CREB (pCREB) in chronic neuropathic pain. Lumbar intrathecal catheters were chronically implanted in male Sprague-Dawley rats. The left sciatic nerve was loosely ligated proximal to the sciatica’s trifurcation at around 1.0- mm intervals with 4-0 silk suture. Mitogen-activated protein kinase kinase (MEK) inhibitor U0126 and phosphorothioate-modified antisense oligonucleotides (ODN) were intrathecally administered one day before and three consecutive days after CCI. Thermal and mechanical nociceptive thresholds were assessed with the paw withdrawal lantency (PWL) to radiant heat and von Frey filaments respectively. The expression of pCREB and Fos were assessed by both Western blot and immunohistochemical analysis. The results showed that intrathecal injection of U0126 or ERK antisense ODN attenuated significantly CCI-induced mechanical and thermal hyperalgesia. Correlating with behavior results, the injection also markedly suppressed the increase of CCI-induced pCREB and c-Fos expression. The results obtained suggest that CREB participates in the pERK-mediated neuropathic pain.

Key words: cAMP response-element binding protein; neuropathic pain; c-fos; extracellular signal-regulate kinase

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通讯作者：曹君利　　E-mail: caojl0310@163.com

引用本文：

宋雪松, 徐艳冰, 曹君利, 何建华, 张励才, 曾因明. cAMP 反应元件结合蛋白介导磷酸化细胞外信号调节激酶 在神经病理性痛形成中的作用[J]. 生理学报 2005; 57 (2): 139-146.

SONG Xue-Song, XU Yan-Bing, CAO Jun-Li, HE Jian-Hua, ZHANG Li-Cai, ZENG Yin-Ming. cAMP response-element binding protein participates in the phosphorylated extracellular signal-regulate kinase mediated neuropathic pain. Acta Physiol Sin 2005; 57 (2): 139-146 (in Chinese with English abstract).