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 "braking signals" in inflammation. The present study investigated the effect of 5 (S), 6 (R)-lipoxin A(4) methyl ester (LXA(4)ME), a stable synthetic analog of lipoxin A(4), 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, LXA(4)ME 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 LXA(4)ME during the induction of morphine tolerance inhibited the activation of microglia and astrocytes; reduced the expression of proinflammatory cytokines interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha); upregulated the expression of anti-inflammatory cytokines IL-10 and transforming growth factor-beta 1 (TGF-beta 1); and inhibited nuclear factor-kappa B (NF-kappa B) activation at the L5 lumbar spinal cord. These results suggest that treatment of LXA(4)ME provides a potential preventative or therapeutic approach for morphine tolerance and associated abnormal pain sensitivity. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.