Nonstereoselective inhibition of neuronal nicotinic acetylcholine receptors by ketamine isomers

We have found that racemic ketamine strongly inhibits the current mediated through neuronal nicotinic acetylcholine receptors (nAchRs) in PC12 cells, a rat pheochromocytoma cell line. Ketamine stereoisomers have different pot encies for the anesthetic action, with the S-enantiomer being about 3 times as potent as the R-enantiomer. The purpose of this study was to clarify if the inhibitory effects of ketamine on neuronal nAchRs contribute to their anesthetic effect. We compared potencies of ketamine enantiomers for neuron al nAchR inhibition with those for the anesthetic action. S(+) and R(-) ket amine inhibited the nicotine-induced whole-cell current in a dose-dependent manner at the membrane potential of -60 mV. They accelerated the current d ecay, resulting in the larger effects on the nondesensitized current than o n the peak current. There was no significant difference in the concentratio ns for 50% inhibition between the stereoisomers. The ketamine isomers exert ed the same effects on single-channel properties estimated from analysis of the nicotine-induced current noise. These results indicate that the inhibi tory action of ketamine isomers on neuronal nAchRs is not stereoselective. Although our findings do not deny possible involvement of these receptors i n ketamine anesthesia, they suggest that inhibition of neuronal nAchRs is n ot primarily responsible for the anesthetic action of this anesthetic.