title: Lipoxin A4 analog attenuates morphine antinociceptive tolerance, withdrawal-induced hyperalgesia, and glial reaction and cytokine expression in the spinal cord of rat.
abstract: 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 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-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α); upregulated the expression of anti-inflammatory cytokines IL-10 and transforming growth factor-β1 (TGF-β1); and inhibited nuclear factor-kappa B (NF-κB) 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.
authors.affiliation: Department of Anesthesiology, Kunhua Hospital, The First People's Hospital of Yunnan Province, Kunming 650032, PR China. jinghuakm@163.com
authors.forename: H
authors.initials: H
authors.lastname: Jin
authors.forename: Y H
authors.initials: YH
authors.lastname: Li
authors.forename: J S
authors.initials: JS
authors.lastname: Xu
authors.forename: G Q
authors.initials: GQ
authors.lastname: Guo
authors.forename: D L
authors.initials: DL
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Bo
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D016207:Cytokines / Q000096:biosynthesis*; D004361:Drug Tolerance / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D006930:Hyperalgesia / Q000139:chemically induced / Q000517:prevention & control*; D007278:Injections, Spinal; D044045:Lipoxins / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D016328:NF-kappa B / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects*; D010147:Pain Measurement / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D013375:Substance Withdrawal Syndrome / Q000517:prevention & control*
chemical_list: D000701:Analgesics, Opioid; D016207:Cytokines; D044045:Lipoxins; D016328:NF-kappa B; C040527:lipoxin A4; C573617:lipoxin A4 methyl ester; D009020:Morphine