纳洛酮脑保护作用的研究现状
1.5 改变细胞内镁的浓度
镁离子是目前较为确定的内源性脑保护因子，Vink和Heath等用磁共振分光技术测量发现实验性液压伤后脑组织神经细胞游离镁离子含量即刻下降，仅为伤前的60%左右，以损伤区下降最显著，全脑组织镁离子含量下降13%，且镁离子下降程度与伤情呈线性相关。纳洛酮能增加κ受体的活性，快速应用可以限制脊髓外伤后组织学改变和神经功能障碍的进一步发展[13, 14]。Vink等发现，外伤后30 min内纳洛酮治疗较生理盐水对照组能明显改善伤后4周的神经功能恢复，其原因是在纳洛酮治疗早期可增加细胞内镁的浓度，二磷酸腺苷浓度和细胞磷酸化电位也均有显著改善，随之改善神经细胞的生物能量代谢状况[15]。 2 纳洛酮能改善应激状态下脑组织的病理生理紊乱 急性颅脑外伤等严重应激状态下，机体骤然释放大量内源性阿片肽抑制儿茶酚胺和前列腺素对心血管和微循环的调节，能导致广泛的病理生理效应，如脑灌注压下降、脑组织缺血缺氧、呼吸抑制以及意识障碍加重。脑血流的改变与急性重症脑损伤后出现的血粘度升高、红细胞聚集、血流速度改变以及血管痉挛等有关。上述病理生理改变进一步加重继发性神经损害。临床研究结果也证明，急性脑损伤病人伤后β-EP含量明显增高，其增高的程度与伤情轻重和意识障碍程度呈正相关；动态监测β-EP水平变化可以反映机体的病理生理改变和预测病人的预后[16, 17]。
Mcintoch等报道，纳洛酮治疗也可改善伤后运动神经功能恢复。纳洛酮与中枢神经系统的μ、κ和δ受体结合，具有麻醉催醒及解除呼吸抑制的作用。使病人存活质量明显提高，致残率降低。对抗内源性阿片肽引起的应激性病理生理改变具有起效快、作用可靠的优点[18-20]。纳洛酮竞争性阻断内源性阿片肽与中枢和外周神经的阿片受体结合，其可能的神经保护作用机制有：（1）抑制软膜血管收缩，增加脑血流和脑灌注压；（2）抑制缺血时细胞膜脂质分解代谢，抑制氧自由基的产生和抗脂质过氧化作用，增加细胞膜的稳定性；（3）改善缺血时神经细胞内Ca2+、Mg2+紊乱，恢复线粒体氧化磷酸化和能量供给；（4）抑制脑损伤时小胶质细胞的活化，减少炎症介质产生和级联反应；（5）降低ET、提高降钙素基因相关肽水平保护神经元；（6）减轻心血管神经中枢功能抑制，抑制外周血管平滑肌收缩，从而调节血压，改善创伤后休克状况等作用机制，逆转β-EP对中枢神经系统的抑制和损害[7, 21]。
另外，纳洛酮治疗脑外伤的量效关系非常复杂，可能与内源性阿片肽及其受体与脑外伤之间关系复杂有关。Hayes等发现，小剂量纳洛酮明显加重颅脑外伤动物伤后运动神经功能障碍；相反，阿片受体类似物吗啡可明显减轻颅脑外伤动物伤后运动神经功能障碍[22]。Flamm等也发现对于急性脊髓损伤的病人，小剂量纳洛酮对体感诱发电位无任何改善，而大剂量纳洛酮则可明显改善体感诱发电位。近年来的研究结果表明，μ和δ受体对颅脑损伤具有保护作用[23]。动物实验结果表明，纳洛酮较小剂量时主要产生μ受体阻断效应，大剂量时才拮抗κ、δ受体，产生更强的神经保护作用。存在纳洛酮治疗的这种量效关系的具体机制目前还不是特别清楚，估计与颅脑外伤后各种阿片类物质升高的时间、速度、幅度、持续时间以及不同剂量纳洛酮与几种受体亲和力不同有关。 3 结论 总之，纳洛酮能竞争性阻断内源性阿片肽对神经功能的损害作用，减少自由基的产生、小胶质细胞活化和炎症介质的释放，改善神经细胞的能量代谢，逆转钙离子、兴奋性氨基酸升高等对神经系统的损害作用，并可能增加内源性脑保护因子的活性而达到神经保护的作用。但其具体的作用机制和临床疗效仍需要进一步观察。
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