Open AccessDexamethasone and potassium canrenoate alleviate hyperalgesia by competitively regulating IL‐6/JAK2/STAT3 signaling pathway during inflammatory pain in vivo and in vitro
Author(s) -
Liu Jie,
Xie Xiaolan,
Qin Kai,
Xu Le,
Peng Juxiang,
Li Xiangyu,
Li Xiongjuan,
Liu Zhiheng
Publication year - 2022
Publication title -
immunity, inflammation and disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 18
ISSN - 2050-4527
DOI - 10.1002/iid3.721
Subject(s) - pharmacology , agonist , ovariectomized rat , in vivo , mineralocorticoid receptor , hyperalgesia , chemistry , glucocorticoid receptor , dexamethasone , nociception , antagonist , receptor , endocrinology , medicine , biology , biochemistry , microbiology and biotechnology , hormone
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, pSTAT3 Ser727 , 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 pSTAT3 Ser727 . The molecular docking study demonstrated that both Dexa and Cane displayed a firm interaction with THR 138 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.