Activation of the spinal ERK signaling pathway contributes naloxone-precipitated withdrawal in morphine-dependent rats
Activation of the spinal ERK signaling pathway contributes naloxone-precipitated withdrawal in morphine-dependent rats
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脊髓 ERK 信号通路的激活导致吗啡依赖大鼠纳洛酮诱发戒断
DOI：
10.1016/j.pain.2005.09.006
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发表时间：
2005-12-05
期刊：
影响因子：
7.4
通讯作者：
Zeng, YV
中科院分区：
文献类型：
--
作者：
Cao, JL;He, JH;Zeng, YV
细胞外信号调节激酶 (ERK) 是一种丝裂原激活蛋白激酶 (MAPK)，可将广泛的细胞外刺激转化为不同的细胞内反应。最近的研究表明，脊髓上水平的ERK激活参与了药物依赖，特别是心理依赖的发展。在这项研究中，我们报道了长期注射吗啡可以激活脊髓 ERK 信号通路。纳洛酮沉淀戒断后，ERK 激活进一步增加。此外，通过鞘内注射 MAPK 激酶 (MEK) 抑制剂 U0126 减弱脊髓 ERK 磷酸化或通过反义寡核苷酸敲低脊髓 ERK，不仅可以降低吗啡戒断评分，还可以减轻戒断引起的异常性疼痛，同时伴随脊髓中 ERK 磷酸化的降低。脊髓 ERK 抑制或敲低还降低吗啡戒断诱导的 cAMP 反应元件结合蛋白 (CREB) 磷酸化和 Fos 表达，cAMP 反应元件结合蛋白 (CREB) 是 ERK 通路的重要下游底物之一。我们的发现支持脊髓 ERK 参与吗啡戒断，鞘内注射 N-甲基-D-天冬氨酸受体拮抗剂 MK-801 或蛋白激酶 C 抑制剂氯化白屈菜红碱可抑制戒断诱导的脊髓 ERK 激活，并减轻吗啡戒断症状。这些发现表明，脊髓 ERK 信号通路的激活有助于吗啡依赖大鼠中纳洛酮的戒断。 (c) 2005 年国际疼痛研究协会。由 Elsevier B.V. 出版。保留所有权利。
Extracellular signal-regulated kinase (ERK), a mitogen-activated protein kinases (MAPK), transduces a broad range of extracellular stimuli into diverse intracellular responses. Recent studies have showed that ERK activation in the supraspinal level involved in the development of drug dependence, especially in psychological dependence. In this study, we reported that the spinal ERK signaling pathway was activated by chronic morphine injection. There was a further increase in ERK activation after naloxone-precipitated withdrawal. Furthermore, attenuation of the spinal ERK phosphorylation by intrathecal a MAPK kinase (MEK) inhibitor U0126 or knockdown of the spinal ERK by antisense oligonucleotides not only decreased the scores of morphine withdrawal, but also attenuated withdrawal-induced allodynia, which were accompanied by decreased ERK phosphorylation in the spinal cord. The spinal ERK inhibition or knockdown also reduced morphine withdrawal-induced phosphorylation of cAMP response element binding protein (CREB), which is one of the important downstream substrates of ERK pathway, and Fos expression. The involvement of the spinal ERK in morphine withdrawal was supported by our finding that intrathecal N-methyl-D-aspartate receptor antagonist MK-801 or protein kinase C inhibitor chelerythrine chloride suppressed withdrawal-induced ERK activation in the spinal cord and attenuated morphine withdrawal symptoms. These findings suggest activation of the spinal ERK signaling pathway contributes naloxone-precipitated withdrawal in morphine-dependent rats. (c) 2005 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.