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Besides its general anesthetic effect, ketamine has local anesthetic-like actions. We studied the voltage- and use-dependent interaction of S(+)- and R(−)-ketamine with two different isoforms of voltage-operated sodium channels, with a special emphasis on the difference in affinity between resting and inactivated channel states. Rat brain IIa and human skeletal muscle sodium channels were heterologously expressed in human embryonic kidney 293 cells. S(+)- and R(−)-ketamine reversibly suppressed whole-cell sodium inward currents; the 50% inhibitory concentration values at −70 mV holding potential were 240 ± 60 μM and 333 ± 93 μM for the neuronal isoform and 59 ± 10 μM and 181 ± 49 μM for the skeletal muscle isoform. S(+)-ketamine was significantly more potent than R(−)-ketamine in the skeletal muscle isoform only. Ketamine had a higher affinity to inactivated than to resting channels. However, the estimated difference in affinity between inactivated and resting channels was only 8- to 10-fold, and the time course of drug equilibration between inactivated and resting channels was too fast to cause use-dependent block at 10 Hz up to a concentration of 300 μM. These results suggest that ketamine is less effective than lidocaine-like local anesthetics in stabilizing the inactivated channel state.