Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Gwangju, South Korea.
J Neurosurg Anesthesiol. 2012 Jan;24(1):51-7. doi: 10.1097/ANA.0b013e3182368d70.
Opioid agonists have been implicated in neuroprotection from hypoxic injury through regulating mitogen-activated protein kinases and cytokines. We determined the effects of remifentanil in focal brain ischemia and reperfusion (I/R) injury. Mechanisms linked to mitogen-activated protein kinases, including extracellular signaling-regulated kinase (ERK) 1/2, p38 kinases, and c-Jun N-terminal kinase (JNK), and various cytokines were also examined.
Male Sprague-Dawley rats were subjected to an I/R insult consisting of 90 minutes' middle cerebral artery occlusion (MCAO) followed by reperfusion under general anesthesia. Neurological deficit scores and infarct volume were determined after 24 hours of reperfusion. Remifentanil (5 μg/kg/min) was given alone or combined with naltrindole (δ-opioid receptor antagonist; 1 mg/kg), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (μ-opioid receptor antagonist; 1 mg/kg), or 5'-guanidinonaltrindole (κ-opioid receptor antagonist; 1 mg/kg). Opioid antagonists were administered 20 minutes before MCAO. Remifentanil infusion was started 10 minutes before MCAO and continued throughout. The control group was without drugs. The expression levels of ERK1/2, p38, and JNK, and also those of tumor necrosis factor-α (TNF-α) and interleukin-6, were determined after 1, 3, and 24 hours of reperfusion.
Remifentanil significantly improved the functional outcome and reduced the infarct volumes (69.0±24.3 mm(3) vs. 108.9±24.8 mm(3)), which were not affected by D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) or 5'-guanidinonaltrindole, but were abolished by naltrindole. The I/R insult enhanced the phosphorylation of ERK 1/2 and the expression of TNF-α, which were significantly reduced by remifentanil. Neither the phosphorylation of p38 and JNK nor the production of interleukin-6 was altered throughout the experiment.
Remifentanil may be neuroprotective against focal I/R injury, possibly through the activation of δ-opioid receptors and attenuation of ERK 1/2 activity and TNF-α production, in the rat brain.
阿片类激动剂通过调节丝裂原活化蛋白激酶和细胞因子，被认为对缺氧损伤具有神经保护作用。我们确定了瑞芬太尼在局灶性脑缺血再灌注（I / R）损伤中的作用。还检查了与丝裂原活化蛋白激酶（包括细胞外信号调节激酶（ERK）1 / 2、p38 激酶和 c-Jun N 末端激酶（JNK））相关的各种机制以及各种细胞因子。
雄性 Sprague-Dawley 大鼠接受 90 分钟大脑中动脉闭塞（MCAO）和全身麻醉下再灌注组成的 I / R 损伤。再灌注 24 小时后测定神经功能缺损评分和梗死体积。瑞芬太尼（5μg/kg/min）单独使用或与纳曲酮（δ-阿片受体拮抗剂；1mg/kg）、D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH（2）（μ-阿片受体拮抗剂；1mg/kg）或 5'-胍基纳曲酮（κ-阿片受体拮抗剂；1mg/kg）联合使用。阿片受体拮抗剂在 MCAO 前 20 分钟给药。瑞芬太尼输注在 MCAO 前 10 分钟开始，并持续进行。对照组无药物。在再灌注后 1、3 和 24 小时测定 ERK1 / 2、p38 和 JNK 的表达水平，以及肿瘤坏死因子-α（TNF-α）和白细胞介素-6 的表达水平。
瑞芬太尼显著改善了功能结果并减少了梗死体积（69.0±24.3mm（3）比 108.9±24.8mm（3）），这不受 D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH（2）或 5'-胍基纳曲酮的影响，但被纳曲酮所消除。I / R 损伤增强了 ERK 1 / 2 的磷酸化和 TNF-α的表达，这两种表达均被瑞芬太尼显著降低。在整个实验过程中，p38 和 JNK 的磷酸化以及白细胞介素-6 的产生均未改变。
瑞芬太尼可能通过激活 δ-阿片受体和减轻 ERK 1 / 2 活性和 TNF-α的产生，对大鼠脑的局灶性 I / R 损伤具有神经保护作用。
