Abstract
Morphine tolerance developed after repeated or continuous morphine treatment is a global health concern hindering the control of chronic pain. In our previous research, we have reported that the expression of lncRNAs and microRNAs have been greatly modified in the spinal cord of morphine tolerated rats, and the modulating role of miR-873a-5p, miR-219-5p and miR-365 have already been confirmed. However, whether circular RNAs, another essential kind of non-coding RNA, are involved in the pathogenesis of morphine tolerance is still beyond our knowledge. In this study, we conducted microarray analysis for circRNA profile and found a large number of circRNAs changed greatly in the spinal cord by morphine treatment. Among them, we selected nine circRNAs for validation, and seven circRNAs are confirmed. Gene Ontology/Kyoto Encyclopedia of Genes and Genomes (GO/KEGG) analysis were used for functional annotation. Besides, we confirmed the modified expression of seven circRNAs after validation by real-time PCR, selected 3 most prominently modulated ones among them and predicted their downstream miRNA-mRNA network and analyzed their putative function via circRNA-miRNA-mRNA pathway. Finally, we enrolled the differentially expressed mRNAs derived from the identical spinal cord, these validated circRNAs and their putative miRNA targets for ceRNA analysis and screened a promising circRNA-miRNA-mRNA pathway in the development of morphine tolerance. This study, for the first time, provided valuable information on circRNA profile and gave clues for further study on the circRNA mechanism of morphine tolerance.
Highlights
Morphine is widely used in the management of acute and chronic pain, and remains among the most effective drugs for moderate and severe pain and escalated cancer pain nowadays
The average level of each Circular RNA (circRNA) in both groups was shown in the scatter plot in Fig. 1d, it is obvious that a large number of circRNAs were significantly modified by morphine treatment
The profile revealed that 896 circRNAs were up-regulated and 1142 circRNAs were downregulated in the lumbar spinal cord tissue after tolerance induction by chronic morphine treatment
Summary
Morphine is widely used in the management of acute and chronic pain, and remains among the most effective drugs for moderate and severe pain and escalated cancer pain nowadays. A major problem that hinders its use is the analgesic tolerance developed after repeated or continuous utility [1,2,3]. We have identified that plenty of microRNAs and lncRNAs were dramatically modified in the lumbar spinal cord of rats with morphine tolerance, suggesting the non-coding RNAs may have extensive effect in this condition [12,13,14]. Though recently circRNAs have been documented to encode proteins, most studies reveal their major role as non-coding RNAs exerting transcriptional and post-transcriptional regulatory effects [18,19,20]. Similar to other non-coding RNAs, circRNAs have been considered valuable in understanding the pathogenesis of diseases and developing diagnostic biomarkers for diseases [21]
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