AMPK-autophagy-mediated inhibition of microRNA-30a-5p alleviates morphine tolerance via SOCS3-dependent neuroinflammation suppression

  • J Neuroinflammation. 2022 Jan 29;19(1):25. doi: 10.1186/s12974-022-02384-3.
Li Wan   #  1 ,  Ru-Meng Jia   #  1 ,  Lu-Lu Ji   #  1 ,  Xin-Miao Qin  1 ,  Liang Hu  1 ,  Fan Hu  1 ,  Yuan Han  2 ,  Yin-Bing Pan  3 ,  Chun-Yi Jiang  4 ,  Wen-Tao Liu  5
Affiliations
  • 1. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
  • 2. Department of Anesthesiology, Eye & ENT Hospital, Fudan University, Shanghai, 200031, China.
  • 3. Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
  • 4. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. [email protected].
  • 5. Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, 211166, Jiangsu, China. [email protected].
  • # Contributed equally.
PMID: 35093117 DOI: 10.1186/s12974-022-02384-3
Abstract

Background: The development of morphine tolerance is a clinical challenge for managing severe pain. Studies have shown that neuroinflammation is a critical aspect for the development of analgesic tolerance. We found that AMPK-autophagy activation could suppress neuroinflammation and improve morphine tolerance via the upregulation of suppressor of cytokine signaling 3 (SOCS3) by inhibiting the processing and maturation of microRNA-30a-5p.

Methods: CD-1 mice were utilized for the tail-flick test to evaluate morphine tolerance. The microglial cell line BV-2 was utilized to investigate the mechanism of AMPK-autophagy-mediated posttranscriptional regulation of SOCS3. Proinflammatory cytokines were measured by western blotting and Real-Time PCR. The levels of SOCS3 and miRNA-processing Enzymes were evaluated by western blotting, Real-Time PCR and immunofluorescence staining.

Results: Based on experimental verification, miRNA-30a-5p could negatively regulate SOCS3. The AMPK activators AICAR, resveratrol and metformin downregulated miRNA-30a-5p. We found that AMPK activators specifically inhibited the processing and maturation of miRNA-30a-5p in microglia by degrading DICER and AGO2 via Autophagy. Furthermore, a miRNA-30a-5p inhibitor significantly improved morphine tolerance via upregulation of SCOS3 in mice. It markedly increased the level of SOCS3 in the spinal cord of mice and subsequently inhibited morphine-induced phosphorylation of NF-κB p65. In addition, a miRNA-30a-5p inhibitor decreased the levels of IL-1β and TNF-α caused by morphine in microglia.

Conclusion: AMPK-autophagy activation suppresses neuroinflammation and improves morphine tolerance via the upregulation of SOCS3 by inhibiting miRNA-30a-5p.

Keywords
AMPK-autophagy; Morphine tolerance; Neuroinflammation; SOCS3; microRNA-30a-5p.
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