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Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions

Abstract

Inflammatory pain, such as arthritis pain, is a growing health problem1. Inflammatory pain is generally treated with opioids and cyclooxygenase (COX) inhibitors, but both are limited by side effects. Recently, resolvins, a unique family of lipid mediators, including RvE1 and RvD1 derived from omega-3 polyunsaturated fatty acid, have shown marked potency in treating disease conditions associated with inflammation2,3. Here we report that peripheral (intraplantar) or spinal (intrathecal) administration of RvE1 or RvD1 in mice potently reduces inflammatory pain behaviors induced by intraplantar injection of formalin, carrageenan or complete Freund's adjuvant (CFA), without affecting basal pain perception. Intrathecal RvE1 injection also inhibits spontaneous pain and heat and mechanical hypersensitivity evoked by intrathecal capsaicin and tumor necrosis factor-α (TNF-α). RvE1 has anti-inflammatory activity by reducing neutrophil infiltration, paw edema and proinflammatory cytokine expression. RvE1 also abolishes transient receptor potential vanilloid subtype-1 (TRPV1)- and TNF-α–induced excitatory postsynaptic current increases and TNF-α–evoked N-methyl-D-aspartic acid (NMDA) receptor hyperactivity in spinal dorsal horn neurons via inhibition of the extracellular signal–regulated kinase (ERK) signaling pathway. Thus, we show a previously unknown role for resolvins in normalizing the spinal synaptic plasticity that has been implicated in generating pain hypersensitivity. Given the potency of resolvins and the well-known side effects of opioids and COX inhibitors, resolvins may represent new analgesics for treating inflammatory pain.

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Figure 1: Preemptive spinal (intrathecal) administration of RvE1 reduces the second phase of formalin-induced inflammatory pain.
Figure 2: Central and peripheral actions of resolvins on persistent inflammatory pain and inflammation.
Figure 3: Spinal administration of RvE1 reduces heat hyperalgesia and spontaneous pain by blocking TRPV1 and TNF-α signaling in DRG neurons and spinal presynaptic terminals.
Figure 4: Spinal RvE1 administration attenuates mechanical allodynia and blocks TNF-α signaling in postsynaptic dorsal horn neurons.

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Acknowledgements

This work was supported in part by US National Institutes of Health grants R01-DE17794 and R01-NS54362 to R.-R.J., R37 GM38765, R01-DE019938 and R01-DK074448 to C.N.S. and NS67686 to both R.-R.J. and C.N.S.

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Authors

Contributions

R.-R.J. and C.N.S. formulated the hypotheses, designed and supervised the project and prepared the manuscript; R.-R.J. designed most experiments; Z.-Z.X., T.L. and J.Y.P. conducted behavioral studies; L.Z. performed electrophysiological studies; Z.-Z.X. and L.Z. performed immunohistochemistry; Z.-Z.X. performed siRNA-mediated knockdown, cytokine arrays and western blotting; T.B. performed in situ hybridization; R.Y. prepared resolvins and their analogs.

Corresponding authors

Correspondence to Charles N Serhan or Ru-Rong Ji.

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Competing interests

Resolvins are biotemplates for stable analogs. Patents on these are awarded and assigned to the Brigham and Women's Hospital, and C.N.S. is the inventor. These patents are licensed for clinical development.

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Xu, ZZ., Zhang, L., Liu, T. et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nat Med 16, 592–597 (2010). https://doi.org/10.1038/nm.2123

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