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Background Prolonged forced abstinence from morphine can increase cue-induced cravings for the drug, contributing to a persistent vulnerability to relapse. Previous studies have identified the implications of aberrant microRNA (miRNA) regulation in the pathogenesis of morphine addiction, but the changes in miRNA expression during the incubation of morphine craving are still unknown. Methods Nucleus accumbens (NAc)-specific altered miRNA transcriptomics was determined in a mouse model of cue-induced incubation of morphine craving following a next-generation sequencing method and verified by RT-qPCR. Bioinformatics analysis was performed to predict the target gene of selected miRNA, and the protein expression of the target gene was detected by western blot. A dual-luciferase assay was performed to confirm the binding sites, and gain- and loss-of-function strategy was applied to understand the mechanism of miRNA and its target gene. Results The miR-592-3p observed to be downregulated in the NAc core was linked to the incubation of morphine craving, and a dual-luciferase assay was performed to confirm the binding sites of miR-592-3p in its target gene, tomoregulin-1 (TMEFF1). Also, gain- and loss-of-function analyses revealed that the inhibition of miR-592-3p expression in the NAc core negatively regulated TMEFF1 expression, thereby enhancing the incubation of morphine craving; however, the overexpression of miR-592-3p in the NAc core resulted in a decreased expression of TMEFF1 , thereby reducing the incubation of morphine craving. Conclusion Our findings demonstrated that miR-592-3p can improve the incubation of morphine craving by targeting TMEFF1 , and thus, it holds a therapeutic potential to inhibit opioid craving. [ABSTRACT FROM AUTHOR]

Reconsolidation of drug memories is the process of restoring unstable memories after unconditioned (UCS; e.g., drugs) or conditioned stimulus (CS; e.g., drug-paired contexts), and provides promise for prevention of drug relapse. Circular RNAs (circRNAs) have important effects on the transcription and post-transcriptional regulation of gene expression. However, the role of circRNAs in the reconsolidation of drug memories is unclear. Here, we observed that cocaine-induced memory retrieval significantly increased circTmeff-1 level in the nucleus accumbens (NAc) core but not shell. Importantly, the disrupted expression of circTmeff-1 using virus in the NAc core damaged the reconsolidation of cocaine-associated memories. The knockdown of circTmeff-1 in the NAc shell or without UCS retrieval or 9 h after UCS retrieval had no such effects. Mechanistically, using bioinformatic analysis and loss- or gain- of function assays, we revealed that antagomiR-206 reversed the inhibitory effect of circTmeff-1 knockdown on the expression of brain-derived neurotrophic factor (BDNF) during the reconsolidation of cocaine-associated memories. Taken together, these results demonstrate the role of circTmeff-1 in the reconsolidation of cocaine-associated memory and that circTmeff-1 may function as a decoy for miR-206 to regulate the expression of BDNF. [Display omitted] • The UCS retrieval increased circTmeff-1 expression in the NAc core but not shell. • Knockdown of circTmeff-1 damages UCS-induced reconsolidation of memory. • Circtmeff-1 regulates the expression of miR-206 and BDNF. [ABSTRACT FROM AUTHOR]