Abstract
Lipoxins and resolvins have anti-inflammatory and pro-resolving actions and accumulating evidence indicates that these lipid mediators also attenuate pain-like behavior in a number of experimental models of inflammation and tissue injury-induced pain. The present study was undertaken to assess if spinal administration of lipoxin A4 (LXA4) or 17 (R)-resolvin D1 (17(R)-RvD1) attenuates mechanical hypersensitivity in the carrageenan model of peripheral inflammation in the rat. Given the emerging role of spinal cytokines in the generation and maintenance of inflammatory pain we measured cytokine levels in the cerebrospinal fluid (CSF) after LXA4 or 17(R)-RvD1 administration, and the ability of these lipid metabolites to prevent stimuli-induced release of cytokines from cultured primary spinal astrocytes. We found that intrathecal bolus injection of LXA4 and17(R)-RvD1 attenuated inflammation-induced mechanical hypersensitivity without reducing the local inflammation. Furthermore, both LXA4 and 17(R)-RvD1 reduced carrageenan-induced tumor necrosis factor (TNF) release in the CSF, while only 17(R)-RvD1attenuated LPS and IFN-γ-induced TNF release in astrocyte cell culture. In conclusion, this study demonstrates that lipoxins and resolvins potently suppress inflammation-induced mechanical hypersensitivity, possibly by attenuating cytokine release from spinal astrocytes. The inhibitory effect of lipoxins and resolvins on spinal nociceptive processing puts them in an intriguing position in the search for novel pain therapeutics.
Highlights
Inflammatory mediators released subsequent to nerve and tissue injury are instrumental for the induction, enhancement and propagation of pain
The present study demonstrates that injection of lipoxin A4 (LXA4) and 17(R)-resolvin D1 (RvD1) into the cerebrospinal fluid (CSF) reduces inflammation-induced mechanical hypersensitivity
Carrageenan-induced inflammation leads to spinal release of tumor necrosis factor (TNF), which was prevented by i.t. pretreatment with LXA4 and 17(R)-RvD1
Summary
Inflammatory mediators released subsequent to nerve and tissue injury are instrumental for the induction, enhancement and propagation of pain. Cytokines and chemokines regulate nociceptive mechanisms both in the peripheral and central nervous system, and for example, blockage of spinal TNF-α and IL-1β actions attenuates persistent pain behavior in a number of different experimental models of pain (reviewed in 22). From an intracellular perspective, signaling through the NFκB and mitogen activated protein kinase (MAPK) pathways is altered in the presence of lipoxins and resolvins [25,26,27,28,29,30] These pathways are activated in the spinal cord subsequent to peripheral inflammation and have been linked to spinal cytokine and chemokine production [31]. Given that FPR2/ALX is expressed in astrocytes, we examined if LXA4 or 17(R)-RvD1 attenuated stimulus-induced TNF release in rat primary astrocyte cell cultures
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