Hronova Anna, Pritulova Eliska, Hejnova Lucie, Novotny Jiri
Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic.
Int J Mol Sci. 2025 May 4;26(9):4371. doi: 10.3390/ijms26094371.
N6-methyladenosine (mA) is one of the most prevalent methylated modifications of mRNA in eukaryotes. This reversible alteration can directly or indirectly influence biological functions, including RNA degradation, translation, and splicing. This study investigates the impact of chronic morphine administration and varying withdrawal durations (1 day, 1 week, 4 weeks, and 12 weeks) on the mA modification levels in brain regions critical to addiction development and persistence. Our findings indicate that in the prefrontal cortex, the mA levels and METTL3 expression decrease, accompanied by an increase in FTO and ALKBH5 expression, followed by fluctuating, but statistically insignificant changes in methylation-regulating enzymes over prolonged withdrawal. In the striatum, reductions in mA levels and METTL3 expression are observed at 4 weeks of withdrawal, preceded by non-significant fluctuations in enzyme expression and the mA modification levels. In contrast, no changes in the mA modification levels or the expression of related enzymes are detected in the hippocampus and the cerebellum. Our data suggest that mA modification and its regulatory enzymes undergo region-specific and time-dependent changes in response to chronic morphine exposure and subsequent withdrawal.
N6-甲基腺苷（mA）是真核生物中mRNA最普遍的甲基化修饰之一。这种可逆性改变可直接或间接影响生物学功能，包括RNA降解、翻译和剪接。本研究调查了长期给予吗啡以及不同戒断时长（1天、1周、4周和12周）对成瘾发展和持续存在至关重要的脑区中mA修饰水平的影响。我们的研究结果表明，在额叶前皮质中，mA水平和METTL3表达降低，同时FTO和ALKBH5表达增加，随后在长期戒断过程中，甲基化调节酶出现波动，但无统计学意义的变化。在纹状体中，戒断4周时观察到mA水平和METTL3表达降低，之前酶表达和mA修饰水平有不显著的波动。相比之下，在海马体和小脑中未检测到mA修饰水平或相关酶表达的变化。我们的数据表明，mA修饰及其调节酶在慢性吗啡暴露及随后的戒断反应中会发生区域特异性和时间依赖性变化。
