Journal
JOURNAL OF NEUROINFLAMMATION
Volume 19, Issue 1, Pages -Publisher
BMC
DOI: 10.1186/s12974-022-02384-3
Keywords
Morphine tolerance; AMPK-autophagy; microRNA-30a-5p; SOCS3; Neuroinflammation
Categories
Funding
- National Natural Science Foundation of China [81870870, 81971047]
- Major Project of Science and Technology Innovation Fund of Nanjing Medical University [2017NJMUCX004]
- Key R&D Program (Social Development) Project of Jiangsu Province [BE2019732]
- Nanjing Special Fund for Health Science and Technology Development [YKK19170]
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This study found that AMPK-autophagy activation can suppress neuroinflammation and improve morphine tolerance by upregulating SOCS3 through the inhibition of miRNA-30a-5p.
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-kappa B p65. In addition, a miRNA-30a-5p inhibitor decreased the levels of IL-1 beta and TNF-alpha 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.
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