Blocking mechanisms of ketamine and its enantiomers in enzymatically demyelinated peripheral nerve as revealed by single-channel experiments

Abstract

Background: Ketamine shows, besides its general anesthetic effect, a local anesthetic-like action that is due to blocking of peripheral nerve sodium currents. In this study, the stereoselectivity of the blocking effects of the ketamine enantiomers S(+) and R(-) was investigated in sodium and potassium channels in peripheral nerve membranes. Methods: Ion channel blockade of ketamine was investigated in enzymatically dissociated Xenopus sciatic nerves in multiple-channel and in single-channel outside-out patches. Results: Concentration-effect curves for the Na peak current revealed half- maximal inhibiting concentrations (IC50) of 347 μM and 291 μM for S(+) and R(-) ketamine, respectively. The potential-dependent K current was less sensitive than the Na current with IC50 values of 982 μM and 942 μM. The most sensitive ion channel was the flickering background K channel, with IC50 values of 168 μM and 146 μM for S(+) and R(-) ketamine. Competition experiments suggest one binding site at the flicker K channel, with specific binding affinities for each of the enantiomers. For the Na channel, the block was weaker in acidic (pH 6.6) than in neutral (pH = 7.4) and basic (pH 8.2) solutions; for the flicker K channel, the block was weaker in acidic and stronger in basic solutions. Conclusions: Ketamine blockade of sodium and potassium channels in peripheral nerve membranes shows no stereoselectivity except for the flicker K channel, which showed a very weak stereoselectivity in favor of the R(-) form. This potential-insensitive flicker K channel may contribute to the resting potential. Block of this channel and subsequent depolarization of the resting membrane potential leads, besides to direct Na+ channel block, to inexcitability via Na+ channel inactivation.