BLOCKING MECHANISMS OF KETAMINE AND ITS ENANTIOMERS IN ENZYMATICALLY DEMYELINATED PERIPHERAL-NERVE AS REVEALED BY SINGLE-CHANNEL EXPERIMENTS

Background: Ketamine shows, besides its general anesthetic effect, a l ocal anesthetic-like action that is due to blocking of peripheral nerv e sodium currents. In this study, the stereoselectivity of the blockin g effects of the ketamine enantiomers S(+) and R(-) was investigated i n sodium and potassium channels in peripheral nerve membranes. Methods : Ion channel blockade of ketamine was investigated in enzymatically d issociated Xenopus sciatic nerves in multiple-channel and in single-ch annel outside-out patches. Results: Concentration-effect curves for th e Na+ peak current revealed half-maximal inhibiting concentrations (IC 50) of 347 mu M and 291 mu M for S(+) and R(-) ketamine, respectively, The potential-dependent K+ current was less sensitive than the Na+ cu rrent with IC50 values of 982 mu M and 942 mu M. The most sensitive io n channel was the Bickering background K+ channel, with IC50 values of 168 mu M and 146 mu M for S(+) and R(-) ketamine. Competition experim ents 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) a nd basic (pH = 8.2) solutions; for the flicker K+ channel, the block w as weaker in acidic and stronger in basic solutions. Conclusions: Keta mine blockade of sodium and potassium channels in peripheral nerve mem branes shows no stereoselectivity except for the flicker K+ channel, w hich showed a very weak stereoselectivity in favor of the R(-) form. T his potential-insensitive flicker K+ channel may contribute do the res ting potential. Block of this channel and subsequent depolarization of the resting membrane potential leads, besides to direct Na+ channel b lock, to inexcitability via Na+ channel inactivation.