Lipoxin A₄ analog attenuates morphine antinociceptive tolerance, withdrawal-induced hyperalgesia, and glial reaction and cytokine expression in the spinal cord of rat

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• 作者：H. Jin^a ; ^{jinghuakm@163.com} ; Y.-H. Li^a ; J.-S. Xu^b ; G.-Q. Guo^a ; D.-L. Chen^a ; Y. Bo^a
• 关键词：lipoxin A4 ; morphine ; inflammation ; tolerance
• 刊名：Neuroscience
• 出版年：2012
• 期刊代码：50_03064522
• 类别：neu
• 出版时间：19 April, 2012
• 卷：208
• 期：Complete
• 页码：1-10
• 文件大小：1803 K

摘要

Spinal neuroinflammation has been shown to play an important role in the development of morphine tolerance and morphine withdrawal-induced hyperalgesia. Lipoxins are endogenous lipoxygenase-derived eicosanoids that can function as 鈥渂raking signals鈥?in inflammation. The present study investigated the effect of 5 (S), 6 (R)-lipoxin A₄ methyl ester (LXA₄ME), a stable synthetic analog of lipoxin A₄, on the expression of antinociceptive tolerance and withdrawal-induced hyperalgesia in chronic morphine-treated rats. Chronic morphine administration through repeated subcutaneous injection induced the development of hyperalgesia and the expression of spinal antinociceptive tolerance to morphine. However, LXA₄ME treatment significantly attenuated the development of hyperalgesia and the expression of spinal antinociceptive tolerance to intrathecal morphine in both mechanical and thermal test. Moreover, the administration of LXA₄ME during the induction of morphine tolerance inhibited the activation of microglia and astrocytes; reduced the expression of proinflammatory cytokines interleukin-1尾 (IL-1尾), IL-6, and tumor necrosis factor-伪 (TNF-伪); upregulated the expression of anti-inflammatory cytokines IL-10 and transforming growth factor-尾1 (TGF-尾1); and inhibited nuclear factor-kappa B (NF-魏B) activation at the L5 lumbar spinal cord. These results suggest that treatment of LXA₄ME provides a potential preventative or therapeutic approach for morphine tolerance and associated abnormal pain sensitivity.