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Abstract
Background and objectives Neuropathic pain is partially refractory to currently available treatments. Although some studies have reported that apoptosis signal-regulating kinase 1 (ASK1) may inhibit chronic pain, the mechanisms underlying this process have not been fully elucidated.
Methods Chronic constriction injury (CCI) of the rat sciatic nerve was used to establish a neuropathic pain model. Nociception was assessed using von Frey hair and Hargreaves’ methods. Western blot and immunofluorescence were used to detect the cell signaling pathway. BV2 cell line was cultured for in vitro evaluation.
Results Our results indicated that spinal ASK1 was co-expressed with the microglia marker ionized calcium binding adaptor 1. Additionally, intrathecal administration of ASK1 inhibitor suppressed the activation of spinal microglia and attenuated CCI-induced neuropathic pain. The ASK1 inhibitor also decreased the levels of phosphorylated ASK1 (p-ASK1), p65, p38 mitogen-activated protein kinase (MAPK) and tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) messenger RNA in lipopolysaccharide-stimulated BV2 microglia cells. Intragastric administration of levo-corydalmine (l-CDL) significantly attenuated CCI-induced neuropathic pain and inhibited the expression of p-ASK1 in the spinal cord. l-CDL conspicuously suppressed the activation of spinal microglia in vitro and in vivo. Translocation of nuclearfactor-kappa B (NF-κB) and upregulation of p-p65, TNF-α, IL-1β were inhibited by l-CDL. Further, the analgesic effects of l-CDL were associated with reduced levels of phosphorylated protein kinase C (PKC γ), c-JunNH2-terminal kinase, and extracellular signal-regulated kinase.
Conclusions This study showed that the expression of ASK1 in spinal microglia and ASK1 inhibitor suppressed microglia activation via suppression of p38 MAPK/NF-κB, which ultimately attenuated CCI-induced neuropathic pain. l-CDL also inhibited the ASK1-P38 MAPK/NF-κB axis to attenuate CCI-induced neuropathic pain.
- levo-Corydalmine (l-CDL)
- chronic constriction injury (CCI)
- neuropathic pain
- microglia
- apoptosis signal-regulating kinase 1 (ASK1)
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Footnotes
Contributors W-L D, B-Y Y and J-H L co-designed the overall study. W-L D and Y-N B performed the immunoassays and behavioral measures. Y-N B and J-F F carried out the cell cultures and performed related assays. W-L D, S-S L and W-L Z analyzed the results and wrote this manuscript. B-Y Y and J-H L revised the manuscript. All authors read and approved the final manuscript.
Funding This work was supported by the National Natural Science Foundation Youth Fund project (81803752), 'Double First-Class' University project (CPU2018GY32), China Postdoctoral Science Foundation (1600020009), Central Colleges Basic Scientific Research Operating Expenses (2632018PY12) and funded by State Key Laboratory of Natural Medicines (SKLNMZZCX201810).
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All experimental protocols were approved by the Animal Experimentation Ethics Committee of China Pharmaceutical University and adhered to the guidelines of the International Association for the Study of Pain.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement No data are available. Many data generated or analyzed during this study are included in this published article for figures. For tables, the data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.