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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 problem. 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 inflammation. 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-alpha (TNF-alpha). 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-alpha-induced excitatory postsynaptic current increases and TNF-alpha-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.

SUBMITTER: Xu ZZ

PROVIDER: S-EPMC2866054 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundChronic inflammatory pain significantly reduces the quality of life and lacks effective interventions. In recent years, human umbilical cord mesenchymal stem cells (huc-MSCs)-derived exosomes have been used to relieve neuropathic pain and other inflammatory diseases as a promising cell-free therapeutic strategy. However, the therapeutic value of huc-MSCs-derived exosomes in complete Freund's adjuvant (CFA)-induced inflammatory pain remains to be confirmed. In this study, we investigated the therapeutic effect and related mechanisms of huc-MSCs-derived exosomes in a chronic inflammatory pain model.MethodsC57BL/6J male mice were used to establish a CFA-induced inflammatory pain model, and huc-MSCs-derived exosomes were intrathecally injected for 4 consecutive days. BV2 microglia cells were stimulated with lipopolysaccharide (LPS) plus adenosine triphosphate (ATP) to investigate the effect of huc-MSCs-derived exosomes on pyroptosis and autophagy. Bioinformatic analysis and rescue experiments were used to demonstrate the role of miR-146a-5p/ TRAF6 in regulating pyroptosis and autophagy. Western blotting, RT-qPCR, small interfering RNA and Yo-Pro-1 dye staining were performed to investigate the related mechanisms.ResultsHuc-MSCs-derived exosomes alleviated mechanical allodynia and thermal hyperalgesia in CFA-induced inflammatory pain. Furthermore, huc-MSCs-derived exosomes attenuated neuroinflammation by increasing the expression of autophagy-related proteins (LC3-II and beclin1) and inhibiting the activation of NLRP3 inflammasomes in the spinal cord dorsal horn. In vitro, NLRP3 inflammasome components (NLRP3, caspase1-p20, ASC) and gasdermin D (GSDMD-F, GSDMD-N) were inhibited in BV2 cells pretreated with huc-MSCs-derived exosomes. Western blot and Yo-Pro-1 dye staining demonstrated that 3-MA, an autophagy inhibitor, weakened the protective effect of huc-MSCs-derived exosomes on BV2 cell pyroptosis. Importantly, huc-MSCs-derived exosomes transfected with miR-146a-5p mimic promoted autophagy and inhibited BV2 cell pyroptosis. TRAF6, as a target gene of miR-146a-5p, was knocked down via small-interfering RNA, which increased pyroptosis and inhibited autophagy.ConclusionHuc-MSCs-derived exosomes attenuated inflammatory pain via miR-146a-5p/TRAF6, which increased the level of autophagy and inhibited pyroptosis.

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

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