Roles of miR-592-3p and Its Target Gene, TMEFF1, in the Nucleus Accumbens During Incubation of Morphine Craving.
Roles of miR-592-3p and Its Target Gene, TMEFF1, in the Nucleus Accumbens During Incubation of Morphine Craving.
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miR-592-3p 及其靶基因 TMEFF1 在伏隔核中在吗啡渴望孵化过程中的作用
DOI：
10.1093/ijnp/pyac004
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发表时间：
2022-05-27
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影响因子：
--
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长时间强迫戒断吗啡会增加线索诱导的对药物的渴望，导致持续的复发脆弱性。以往的研究已经证实了microRNA（miRNA）的异常调控在吗啡成瘾发病机制中的作用，但在吗啡渴求潜伏期miRNA表达的变化仍不清楚。在下一代测序方法之后，在吗啡渴求的线索诱导孵育的小鼠模型中确定了黑核（NAc）特异性改变的miRNA转录组学，并通过RT-qPCR验证。通过生物信息学分析预测所选miRNA的靶基因，并采用western blot检测靶基因的蛋白表达。通过双荧光素酶分析确定结合位点，并采用功能获得和功能丧失策略研究miRNA及其靶基因的作用机制。在NAc核心中观察到下调的miR-592- 3 p与吗啡渴求的孵育有关，并进行双荧光素酶测定以确认miR-592- 3 p在其靶基因tomoregulin-1（TMEFF 1）中的结合位点。此外，功能获得和丧失分析显示，NAc核心中miR-592- 3 p表达的抑制负调控TMEFF 1表达，从而增强吗啡渴求的潜伏期;然而，NAc核心中miR-592- 3 p的过表达导致TMEFF 1表达的降低，从而减少吗啡渴求的潜伏期。我们的研究结果表明，miR-592- 3 p可以通过靶向TMEFF 1来改善吗啡渴求的孵化，因此，它具有抑制阿片类药物渴求的治疗潜力。
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. 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. 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. 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.
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DOI：
10.1523/jneurosci.6588-10.2011
发表时间：
2011-04-20
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Ito R;Hayen A
通讯作者：
Hayen A
影响因子：
3.4
作者：
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影响因子：
14.9
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DOI：
10.1523/jneurosci.3027-08.2008
发表时间：
2008-12-03
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
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Lu L
影响因子：
3.4
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通讯作者：
OBRIEN, CP