Immunity, Inflammation and Disease (Nov 2022)

Dexamethasone and potassium canrenoate alleviate hyperalgesia by competitively regulating IL‐6/JAK2/STAT3 signaling pathway during inflammatory pain in vivo and in vitro

  • Jie Liu,
  • Xiaolan Xie,
  • Kai Qin,
  • Le Xu,
  • Juxiang Peng,
  • Xiangyu Li,
  • Xiongjuan Li,
  • Zhiheng Liu

DOI
https://doi.org/10.1002/iid3.721
Journal volume & issue
Vol. 10, no. 11
pp. n/a – n/a

Abstract

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Abstract Background Dexamethasone (Dexa) and potassium canrenoate (Cane) modulate nociceptive behavior via glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) by two mechanisms (genomic and nongenomic pathways). This study was designed to investigate the Dexa‐ or Cane‐mediated nongenomic and genomic effects on mechanical nociception and inflammation‐induced changes in interleukin‐6 (IL‐6) mediated signaling pathway in rats. Methods Freund's complete adjuvant (FCA) was used to trigger an inflammation of the right hind paw in male Sprague–Dawley rats. First, the mechanical nociceptive behavioral changes were examined following intraplantar administration of GR agonist Dexa and/or MR antagonist Cane in vivo. Subsequently, the protein levels of IL‐6, IL‐6Rα, JAK2, pJAK2, STAT3, pSTAT3Ser727, migration inhibitory factor, and cyclooxygenase‐2 were assessed by Western blot following intraplantar injection of Dexa or Cane or the combination. Moreover, the molecular docking studies determined the interaction between Dexa, Cane, and IL‐6. The competition binding assay was carried out using enzyme‐linked immunosorbent assays (ELISA). Results Administration of Dexa and Cane dose‐dependently attenuated FCA‐induced inflammatory pain. The sub‐additive effect of Dexa/Cane combination was elucidated by isobologram analysis, accompanied by decrease in the spinal levels of IL‐6, pJAK2, and pSTAT3Ser727. The molecular docking study demonstrated that both Dexa and Cane displayed a firm interaction with THR138 binding site of IL‐6 via a strong hydrogen bond. ELISA revealed that Dexa has a higher affinity to IL‐6 than Cane. Conclusions There was no additive or negative effect of Dexa and Cane, and they modulate the IL‐6/JAK2/STAT3 signaling pathway through competitive binding with IL‐6 and relieves hypersensitivity during inflammatory pain.

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