Aprepitant Inhibits JNK and p38/MAPK to Attenuate Inflammation in Microglia and Suppresses Inflammatory Pain

Abstract

Background: Substance P (SP) contributes to the pathogenesis of pain by acting on neurokinin‐1 receptor (NK-1R), specialized sensory neurons that detect noxious stimuli. Aprepitant, an antagonist of NK-1R widely used to treat chemotherapy-induced nausea and vomiting. In this study, we assessed aprepitant’s analgesic effect on inflammatory pain in mice and its mechanism of action in spinal cord.Methods: The excitability of DRG neurons treatment with aprepitant was measured using whole-cell patch-clamp recordings. The inflammatory pain model was induced in adult ICR mice by a single dose intraplantar injection of formalin and carrageenan. The mice were treated with aprepitant, and the behavioral tests were measured after the intraperitoneal injection of aprepitant. The morphological changes on inflamed paw tissues were determined by using hematoxylin eosin staining. The mRNA expressions of MCP-1, TNF-α, IL-6, IL-1β, and NF-κBp65 were measured by real-time quantitative PCR analysis. Changes in the protein expression levels were assayed using enzyme linked immunosorbent assay. Western blotting and immunohistochemistry were used to assay the cell signaling.Results: Aprepitant treatment showed a significantly higher AP threshold in vitro. In vivo, the aprepitant showed a significant anti-inflammatory and analgesia effect in the mice with inflammatory pain. After the administration of aprepitant, the paw tissues inflammatory damage was significantly relived. The mRNA levels of MCP-1, TNF-α, IL-6, IL-1β, and NF-κBp65 were down-regulate following aprepitant treatment. Meanwhile, aprepitant significantly suppressed over-expression of proinflammatory cytokines, as well as the phosphorylation of JNK and p38 MAPK in the spinal cord.Conclusions: The present study suggests that the extract of aprepitant attenuates inflammatory pain in mice via suppressing the phosphorylation of JNK and p38, and inhibiting the NF-κB signaling pathway.