Abstract
BackgroundThe 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.MethodsCD-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.ResultsBased 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.ConclusionAMPK-autophagy activation suppresses neuroinflammation and improves morphine tolerance via the upregulation of SOCS3 by inhibiting miRNA-30a-5p.
Highlights
The development of morphine tolerance is a clinical challenge for managing severe pain
Wan et al Journal of Neuroinflammation (2022) 19:25 decade, an increasing number of studies have demonstrated that morphine can trigger neuroinflammation [1], which is characterized by the activation of microglia [2] and the increased production of proinflammatory cytokines, such as IL-1β, Tumor necrosis factor-α (TNF-α) and IL-6 [3,4,5], resulting in the enhancement of synaptic transmission and central sensitization [6]
In the neuroinflammation evoked by morphine, the mitogen-activated protein kinase (MAPK) family, including p38 MAPK and c-Jun N-terminal kinase (JNK), and the Nuclear factor-κB (NF-κB) signaling pathway were activated in microglia
Summary
The development of morphine tolerance is a clinical challenge for managing severe pain. In the neuroinflammation evoked by morphine, the mitogen-activated protein kinase (MAPK) family, including p38 MAPK and c-Jun N-terminal kinase (JNK), and the NF-κB signaling pathway were activated in microglia. Xu et al reported that TAK1 activation was induced in association with the development of morphine tolerance [9]. Numerous studies have reported that morphine causes the activation of microglia by binding with MD-2, a Toll-like receptor 4 (TLR4) accessory protein [10]. It was reported that high mobility group box 1 (HMGB1) contributed to morphine tolerance via the activation of the TLR4/NF-κB pathway [11]. Evidence has shown that morphine-induced HSP70 release activates microglia and triggers TLR4-mediated neuroinflammation by activating HSP70-TLR4-NLRP3 signaling [12]. It is urgent to explore new mechanisms and develop treatment strategies
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