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چکیده
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Introduction: Morphine tolerance is a challenging clinical problem that limits the use of morphine in the pain management. However, mechanisms underlying morphine tolerance remain unclear. According to recent researches, long noncoding RNAs (lncRNAs) might be a novel and promising target involved in changes at gene expression levels related to morphine tolerance and addiction. The striatum is a main target of the mesocorticolimbic dopaminergic pathway, which is involved in rewarding effects of morphine. However, there is no report regarding expression of lncRNAs in the striatum after repeated administrations of morphine. In this study, we aim to examine expression of biologically-relevant lncRNAs in the striatum after repeated subcutaneous injections of morphine in rats. Method: We used male Wistar rats in our study. Morphine (10 mg/kg) was injected twice a day during 8 days for inducing morphine tolerance. A control group received saline (1 ml/kg) during the treatment. We tested animals for induction of morphine tolerance on a hotplate test of analgesia on day 8 of the treatment. Then, each rat was anesthetized, decapitated and the striatum was dissected on an ice-chilled surface. The expression of biologically-relevant lncRNAs to addiction and some other brain diseases, including MALAT1, BC1, H19, MIAT1, Hypothalamus-enriched lncRNA and Cardiac left ventricle-enriched lncRNA was assessed by using a real-time PCR method. We analyzed the hotplate data with a two-way repeated measure ANOVA followed by Holm-Sidak post hoc test. We also converted the Ct values of real time PCR curves to 2-ΔΔCT value, and then used an independent t-test for pairwise between groups comparisons. P<0.05 was considered as statistically significant level. Result: The rats successfully developed morphine tolerance as revealed by the results of the hotplate test of analgesia compared to saline-treated control group (P<0.001). The results of real-time PCR indicated that the expression of MALAT1, H19, and Hypothalamus-enriched lncRNAs significantly decreased, but expression of MIAT1 and Cardiac left ventricle-enriched lncRNAs significantly increased in the striatum of morphine-tolerant rats compared to the control group. No group difference was detected in expression of BC1 lncRNA in the striatum between the experimental groups. Conclusion: According to our knowledge, this is the first report examining the expression of specific biologically-relevant lncRNAs in the striatum of morphine-tolerant rats. Morphine tolerance is associated with changes in the expression of some lncRNAs in the brain. It can be proposed that lncRNAs may have additional functional roles in morphine tolerance and dependence, which need to be investigated.
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