Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice

Abstract

Introduction: Paclitaxel is a chemotherapy drug that is commonly used to treat cancer, but it can cause paclitaxel-induced neuropathic pain (PINP) as a side effect. Resolvin D1 (RvD1) has been shown to be effective in promoting the resolution of inflammation and chronic pain. In this study, we evaluated the effects of RvD1 on PINP and its underlying mechanisms in mice.

Methods: Behavioral analysis was used to assess the establishment of the PINP mouse model and to test the effects of RvD1 or other formulations on mouse pain behavior. Quantitative real-time polymerase chain reaction analysis was employed to detect the impact of RvD1 on 12/15 Lox, FPR2, and neuroinflammation in PTX-induced DRG neurons. Western blot analysis was used to examine the effects of RvD1 on FPR2, Nrf2, and HO-1 expression in DRG induced by PTX. TUNEL staining was used to detect the apoptosis of DRG neurons induced by BMDM conditioned medium. H2DCF-DA staining was used to detect the reactive oxygen species level of DRG neurons in the presence of PTX or RvD1+PTX treated BMDMs CM.

Results: Expression of 12/15-Lox was decreased in the sciatic nerve and DRG of mice with PINP, suggesting a potential involvement of RvD1 in the resolution of PINP. Intraperitoneal injection of RvD1 promoted pain resolution of PINP in mice. Intrathecal injection of PTX-treated BMDMs induced mechanical pain hypersensitivity in naïve mice, while pretreatment of RvD1 in BMDMs prevented it. Macrophage infiltration increased in the DRGs of PINP mice, but it was not affected by RvD1 treatment. RvD1 increased IL-10 expression in the DRGs and macrophages, while IL-10 neutralizing antibody abolished the analgesic effect of RvD1 on PINP. The effects of RvD1 in promoting IL-10 production were also inhibited by N-formyl peptide receptor 2 (FPR2) antagonist. The primary cultured DRG neurons apoptosis increased after stimulation with condition medium of PTX-treated BMDMs, but decreased after pretreatment with RvD1 in BMDMs. Finally, Nrf2-HO1 signaling was additionally activated in DRG neurons after stimulation with condition medium of RvD1+PTX-treated BMDMs, but these effects were abolished by FPR2 blocker or IL-10 neutralizing antibody.

Discussion: In conclusion, this study provides evidence that RvD1 may be a potential therapeutic strategy for the clinical treatment of PINP. RvD1/FPR2 upregulates IL-10 in macrophages under PINP condition, and then IL-10 activates the Nrf2- HO1 pathway in DRG neurons, relieve neuronal damage and PINP.

Keywords: FPR2; Il-10; RvD1; macrophage; paclitaxel.