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

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.

Inhibition of SIRT1 in the nucleus accumbens attenuates heroin addiction-related behavior by decreasing D1 neuronal autophagy

“…Dysregulation of autophagy disrupts neural function by promoting abnormal protein aggregation. Autophagy-related damage is one of the causes of neurodegeneration [8] and plays an important role in addiction to substances, such as morphine [9] and alcohol [10]. LC3I binds to phosphatidylethanolamine after autophagy, forming lipidated LC3Ⅱ, which is localized to autophagosome membranes.…”

“…The dysregulation of autophagy, however, contributes to the development of neurodegenerative diseases [8]. Numerous studies have been conducted on the relationship between autophagy and drug addiction [9,10]. It remains unclear, however, whether autophagy promotes or prevents drug addiction.…”

Transcriptome profiling of microRNAs reveals potential mechanisms of manual therapy alleviating neuropathic pain through microRNA-547-3p-mediated Map4k4/NF-κb signaling pathway

“…Recently, studies on the involvement of miRNAs in pain-related diseases have been rapidly increasing [ 34 , 50 , 51 ]. Currently, they are mainly focused on investigating the roles of individual miRNA in various physiological and pathological conditions as well as on determining whether they could be potential therapeutic targets.…”

“…Recently, studies on the involvement of miRNAs in pain-related diseases have been rapidly increasing [34,50,51]. Currently, they are mainly focused on Fig.…”

Genetically supported causality between gut microbiota, immune cells and morphine tolerance: a two-sample Mendelian randomization study

“…Additionally, recent studies have highlighted the significance of inflammatory factors released by immune cells in relation to MT ( Eidson and Murphy, 2019 ). There is a growing body of research indicating that morphine has the potential to induce neuroinflammation ( Wan et al, 2022 ). This process involves the activation of microglia ( Mélik Parsadaniantz et al, 2015 ) and an increase in the production of proinflammatory cytokines, including IL-1β, TNF-α, CXCL12, IL-33, and IL-6 ( Eidson et al, 2017 ; Bai et al, 2022 ), leading to heightened synaptic transmission and central sensitization ( He et al, 2019 ).…”