Ketamine impairs excitability in superficial dorsal horn neurones by blocking sodium and voltage-gated potassium currents

Ketamine shows, besides its general anaesthetic effect, a potent analgesic effect after spinal administration. We investigated the local anaesthetic-like action of ketamine and its enantiomers in Na+ and K+ channels and their functional consequences in dorsal horn neurones of laminae I–III, which are important neuronal structures for pain transmission receiving most of their primary sensory input from Aδ and C fibres. Combining the patch-clamp recordings in slice preparation with the ‘entire soma isolation’ method, we studied action of ketamine on Na+ and voltage-activated K+ currents. The changes in repetitive firing behaviour of tonically firing neurones were investigated in current-clamp mode after application of ketamine. Concentration–effect curves for the Na+ peak current revealed for tonic block half-maximal inhibiting concentrations (IC50) of 128 μM and 269 μM for S(+) and R(−)-ketamine, respectively, showing a weak stereoselectivity. The block of Na+ current was use-dependent. The voltage-dependent K+ current (KDR) was also sensitive to ketamine with IC50 values of 266 μM and 196 μM for S(+) and R(−)-ketamine, respectively. Rapidly inactivating K+ currents (KA) were less sensitive to ketamine. The block of KDR channels led to an increase in action potential duration and, as a consequence, to lowering of the discharge frequency in the neurones. We conclude that ketamine blocks Na+ and KDR channels in superficial dorsal horn neurones of the lumbar spinal cord at clinically relevant concentrations for local, intrathecal application. Ketamine reduces the excitability of the neurones, which may play an important role in the complex mechanism of its action during spinal anaesthesia. British Journal of Pharmacology (2005) 146, 826–833. doi:10.1038/sj.bjp.0706385