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目的:探讨吗啡(morphine)在神经病理性疼痛中作用下降的表观遗传学机制。方法:42只SD雄性大鼠鞘内置管后随机分为6组(n=7):假手术组(Ⅰ组),坐骨神经慢性卡压(CCI)+生理盐水(NS)1组(Ⅱ组),CCI+5氮杂胞苷(5-aza)组(Ⅲ组),CCI+NS2组(Ⅳ组),CCI+NS+morphine组(Ⅴ组),CCI+5-aza+morphine组(Ⅵ组)。Ⅰ、Ⅱ、Ⅳ、Ⅴ组手术后0-14d每日鞘内注射10μlNS,Ⅲ、Ⅵ组0-14d每日鞘内注射10μl5-aza(10μmol)。CCI后21d取Ⅰ-Ⅲ组脊髓腰膨大检测总体甲基化和μ阿片受体(MOR)mRNA水平;Ⅳ-Ⅵ组鞘内注射10μlNS(Ⅳ组)和30μg吗啡(Ⅴ、Ⅵ组),注射后0,15,30,45,60min测定机械和热痛阈。结果:Ⅱ组脊髓甲基化水平高于Ⅰ、Ⅲ组,MOR表达水平低于Ⅰ、Ⅲ组,Ⅰ、Ⅲ组之间无差异;Ⅴ、Ⅵ组鞘内给予吗啡后30min机械痛阈和热痛阈明显升高,均高于Ⅳ组,Ⅵ组最高。结论:DNA甲基化可能降低了CCI大鼠脊髓MOR表达,从而影响了阿片药物的镇痛作用。
OBJECTIVE: To investigate the epigenetic mechanism of morphine decline in neuropathic pain. Methods: Forty-two male Sprague-Dawley rats were randomly divided into 6 groups (n = 7): sham operation group (group Ⅰ), CCI + NS group 1 (group Ⅱ) CCI + NS + morphine group, CCI + 5-aza + morphine group (Group VI), CCI + 5-aza + morphine group ). Group Ⅰ, Ⅱ, Ⅳ and Ⅴ received intrathecal injection of 10μl of NS from day 0 to day 14 after operation, and 10μl of 5-aza (10μmol) were injected intrathecally into group Ⅲ and Ⅳ on day 0-14. At 21 days after CCI, total methylation and mRNA expression of mu opioid receptor (MOR) were detected by lumbosacral dissection in group I-III. Intrathecal injection of 10μl NS (group Ⅳ) and morphine (Ⅴ, Ⅵ) After 0,15,30,45,60 min determination of mechanical and thermal pain threshold. Results: The methylation level of spinal cord in group Ⅱ was higher than that in group Ⅰ and Ⅲ, the expression level of MOR was lower than that in group Ⅰ and Ⅲ, and there was no difference between group Ⅰ and Ⅲ. The mechanical pain threshold and heat at 30 min after intrathecal administration of Ⅴ and Ⅵ Pain threshold increased significantly, were higher than the Ⅳ group, Ⅵ highest group. Conclusion: DNA methylation may reduce MOR expression in the spinal cord of CCI rats, which may affect the analgesic effect of opioids.