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右美托咪定和瑞马唑仑减轻神经病理性疼痛的机制研究

Mechanism of dexmedetomidine and remimazolam in alleviating neuropathic pain

    摘要
  • 摘要:
    目的 探讨右美托咪定和瑞马唑仑对神经病理性疼痛的治疗效果及其作用机制。
    方法 选取60只SD大鼠设为假手术组(n=12)、脊神经结扎(SNL)+NC组(n=12)、SNL+DEX组(n=12)、SNL+REM组(n=12)和DEX+REM组(n=12)。分析各组大鼠的机械缩足反射阈值(MWT)。采用蛋白质印迹(Western blot)检测疼痛相关蛋白c-Fos的表达水平。采用免疫荧光分析各组大鼠的自噬情况。采用酶联免疫吸附测定(ELISA)检测各组大鼠炎症因子肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、白细胞介素-10(IL-10)的表达水平。分析各组大鼠氧化应激因子的表达水平。采用Western blot分析NFE2L2/NRF2通路相关蛋白的表达水平。
    结果 SNL+DEX组、SNL+REM组和DEX+REM组大鼠的MWT高于SNL+NC组，差异有统计学意义(P < 0.05)。SNL+NC组的c-Fos蛋白表达水平高于SNL+DEX组、SNL+REM组和DEX+REM组，差异有统计学意义(P < 0.05)。SNL大鼠中的LC3、NeuN免疫荧光强度低于假手术大鼠，表明SNL大鼠神经元细胞自噬受损。SNL+DEX组、SNL+REM组和DEX+REM组大鼠的LC3、NeuN免疫荧光强度高于SNL+NC组，差异有统计学意义(P < 0.05)。SNL+DEX组、SNL+REM组和DEX+REM组大鼠的TNF-α、IL-1β、IL-6表达水平低于SNL+NC组，差异有统计学意义(P < 0.05)。SNL+DEX组、SNL+REM组和DEX+REM组的谷胱甘肽(GSH)、过氧化氢酶(CAT)水平高于SNL+NC组，丙二醛(MDA)水平低于SNL+NC组，差异有统计学意义(P < 0.05)。SNL+DEX组、SNL+REM组和DEX+REM组的NFE2L2蛋白表达水平低于SNL+NC组，且DEX+REM组的NFE2L2蛋白表达水平最低，差异有统计学意义(P < 0.05)。
    结论 右美托咪定和瑞马唑仑通过抑制NFE2L2/NRF2通路相关蛋白表达，降低SNL大鼠体内的氧化应激水平，从而减轻神经病理性疼痛。

     

    Abstract:
    Objective To investigate the therapeutic effects and mechanisms of dexmedetomidine and remimazolam on neuropathic pain.
    Methods A total of 60 SD rats were divided into sham operation group (n=12), spinal nerve ligation (SNL)+NC group (n=12), SNL+DEX group (n=12), SNL+REM group (n=12) and DEX+REM group (n=12). Mechanical withdrawal threshold (MWT) was analyzed in each group. The expression level of pain-related protein c-Fos was detected by Western blot. Autophagy was assessed by immunofluorescence analysis. Enzyme-linked immunosorbent assay (ELISA) was used to measure the expression levels of inflammatory factorstumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6) and interleukin-10 (IL-10)of each group. The expression level of oxidative stress factor in each group was analyzed. The expression levels of NFE2L2/NRF2 pathway related proteins were analyzed by Western blot.
    Results MWT in the SNL+DEX, SNL+REM and DEX+REM groups was significantly higher than that in the SNL+NC group (P < 0.05). The expression level of c-Fos protein in the SNL+NC group was significantly higher than that in the SNL+DEX, SNL+REM and DEX+REM groups (P < 0.05). The immunofluorescence intensity of LC3 and NeuN in SNL rats was lower than that in sham operation rats, indicating that autophagy of neurons in SNL rats was damaged. The immunofluorescence intensity of LC3 and NeuN in the SNL+DEX group, SNL+REM group and DEX+REM group were significantly higher than those in the SNL+NC group (P < 0.05). The expression levels of TNF-α, IL-1β and IL-6 in the SNL+DEX group, SNL+REM group and DEX+REM group were significantly lower than those in the SNL+NC group (P < 0.05). Glutathione (GSH) and catalase (CAT) levels in the SNL+DEX, SNL+REM and DEX+REM groups were significantly higher than those in the SNL+NC group, while malondialdehyde (MDA) levels were significantly lower (P < 0.05). The expression levels of NFE2L2 protein in the SNL+DEX, SNL+REM and DEX+REM groups were significantly lower than that in the SNL+NC group, with the lowest level observed in the DEX+REM group (P < 0.05).
    Conclusion Dexmedetomidine and remimazolam can relieve neuropathic pain in SNL rats by inhibiting the expression of NFE2L2/NRF2 pathway-related proteins and decreasing oxidative stress levels.

     

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