Ishibashi H, Kuwano K, Takahama K
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Kumamoto University, 5-1 Oe-Honmachi, 862-0973, Kumamoto, Japan.
Neuropharmacology. 2000 Sep;39(12):2302-8. doi: 10.1016/s0028-3908(00)00092-7.
The effect of dextromethorphan (DM) on the inwardly rectifying K(+) currents mediated by 5-HT(1A) receptors in acutely dissociated dorsal raphe (DR) neurones of rats was studied using nystatin-perforated patch and conventional whole-cell patch recording configurations under voltage-clamp conditions. DM rapidly and reversibly inhibited the K(+) currents induced by 10(-7) M 5-HT in a concentration-dependent manner with a half-maximum inhibitory concentration of 1.43 x 10(-5) M. The inhibitory effect of DM was neither voltage- nor use-dependent. DM caused a suppression of the maximum response of the 5-HT concentration-response curve, thus suggesting a non-competitive type of inhibition. In neurones perfused intracellularly with a pipette-solution containing the nonhydrolyzable GTP analog GTPgammaS, 5-HT activated K(+) currents in an irreversible manner. DM suppressed the current irreversibly activated by intracellular GTPgammaS even in the absence of the agonist. DM also inhibited the inwardly rectifying K(+) currents regulated by alpha(2)-adrenoceptors in freshly isolated rat locus coeruleus neurones. These results suggest that DM may inhibit the G-protein coupled inwardly rectifying K(+) channels, but not the neurotransmitter receptors, in the central nervous system.
采用制霉菌素穿孔膜片钳和传统全细胞膜片钳记录模式，在电压钳条件下，研究了右美沙芬（DM）对大鼠急性分离的中缝背核（DR）神经元中5-羟色胺（5-HT）1A受体介导的内向整流钾电流的影响。DM以浓度依赖的方式快速、可逆地抑制10(-7) M 5-HT诱导的钾电流，半数最大抑制浓度为1.43 x 10(-5) M。DM的抑制作用既不依赖电压也不依赖使用情况。DM抑制了5-HT浓度-反应曲线的最大反应，因此提示为非竞争性抑制类型。在用含有不可水解的鸟苷三磷酸（GTP）类似物GTPγS的微管溶液进行细胞内灌注的神经元中，5-HT以不可逆方式激活钾电流。即使在没有激动剂的情况下，DM也不可逆地抑制由细胞内GTPγS激活的电流。DM还抑制了新鲜分离的大鼠蓝斑神经元中由α(2)-肾上腺素能受体调节的内向整流钾电流。这些结果提示，DM可能在中枢神经系统中抑制G蛋白偶联内向整流钾通道，而不是神经递质受体。
