Neugebauer V, Geisslinger G, Rümenapp P, Weiretter F, Szelenyi I, Brune K, Schaible H G
Department of Physiology, University of Würzburg, FRG.
J Pharmacol Exp Ther. 1995 Nov;275(2):618-28.
The antinociceptive effects of the S(+)-enantiomer of flurbiprofen (potent inhibitor of cyclooxygenase) and the R(-)-enantiomer (500 times less potent) were investigated in the spinal cord of 20 anesthetized rats. In lumbar segments, 20 wide-dynamic-range dorsal horn neurons with knee joint input were recorded extracellularly. After induction of an acute inflammation in the knee joint by kaolin and carrageenan, the neurons developed hyperexcitability consisting of enhanced responses to stimuli applied to the inflamed knee and the noninflamed ankle and an expansion of receptive fields. Intravenous administration of R(-)-flurbiprofen (1-9 mg/kg) and S(+)-flurbiprofen (0.3-9 mg/kg) at 5.5 to 8.5 h after kaolin, dose dependently reduced the neurons' responses to pressure applied to the inflamed knee (18 of 18 neurons) and the noninflamed ankle (17 of 17 neurons) and paw (8 of 8 neurons). R(-)-flurbiprofen decreased the receptive field size in 8 of 16 neurons, S(+)-flurbiprofen in 10 of 16 neurons. The suppressive effects started 3 to 6 min and reached a maximum 9 to 15 min after i.v. administration. S(+)-flurbiprofen was more potent than the R(-)-enantiomer. When injected directly into the knee joint, S(+)-flurbiprofen (50 and 80 micrograms), but not the R(-)-enantiomer (100 and 180 micrograms) reduced the hyperexcitability in 12 of 12 neurons. These results suggest a central site of antinociceptive action for R(-)-flurbiprofen and S(+)-flurbiprofen and an additional peripheral site for S(+)-flurbiprofen. The doses used in these experiments did not produce any sedative effects in rats subjected to behavioral testing.
在20只麻醉大鼠的脊髓中研究了氟比洛芬的S(+)-对映体（环氧化酶的强效抑制剂）和R(-)-对映体（效力低500倍）的抗伤害感受作用。在腰段，细胞外记录了20个接受膝关节传入的广动力范围背角神经元。在用高岭土和角叉菜胶诱导膝关节急性炎症后，这些神经元出现了超兴奋性，表现为对施加于发炎膝关节和未发炎踝关节的刺激反应增强，以及感受野扩大。在高岭土注射后5.5至8.5小时静脉注射R(-)-氟比洛芬（1 - 9毫克/千克）和S(+)-氟比洛芬（0.3 - 9毫克/千克），剂量依赖性地降低了神经元对施加于发炎膝关节（18个神经元中的18个）、未发炎踝关节（17个神经元中的17个）和爪子（8个神经元中的8个）的压力反应。R(-)-氟比洛芬使16个神经元中的8个感受野大小减小，S(+)-氟比洛芬使16个神经元中的10个感受野大小减小。抑制作用在静脉注射后3至6分钟开始，9至15分钟达到最大。S(+)-氟比洛芬比R(-)-对映体更有效。当直接注射到膝关节时，S(+)-氟比洛芬（50和80微克），而非R(-)-对映体（100和180微克），降低了12个神经元中的12个的超兴奋性。这些结果表明R(-)-氟比洛芬和S(+)-氟比洛芬的抗伤害感受作用有一个中枢位点，而S(+)-氟比洛芬还有一个额外的外周位点。这些实验中使用的剂量在接受行为测试的大鼠中未产生任何镇静作用。
