title: Ketamine impairs excitability in superficial dorsal horn neurones by blocking sodium and voltage-gated potassium currents.
abstract: 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 Adelta 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 microM and 269 microM for S(+) and R(-)-ketamine, respectively, showing a weak stereoselectivity. The block of Na+ current was use-dependent. The voltage-dependent K+ current (K(DR)) was also sensitive to ketamine with IC50 values of 266 microM and 196 microM for S(+) and R(-)-ketamine, respectively. Rapidly inactivating K+ currents (K(A)) were less sensitive to ketamine. The block of K(DR) 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 K(DR) 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.
authors.affiliation: Department of Anaesthesiology, Intensive Care Medicine, Pain Therapy, University Clinic, Giessen, Germany.
authors.forename: Rose
authors.initials: R
authors.lastname: Schnoebel
authors.forename: Matthias
authors.initials: M
authors.lastname: Wolff
authors.forename: Saskia C
authors.initials: SC
authors.lastname: Peters
authors.forename: Michael E
authors.initials: ME
authors.lastname: Bräu
authors.forename: Andreas
authors.initials: A
authors.lastname: Scholz
authors.forename: Gunter
authors.initials: G
authors.lastname: Hempelmann
authors.forename: Horst
authors.initials: H
authors.lastname: Olschewski
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000778:Anesthetics, Dissociative / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D007649:Ketamine / Q000494:pharmacology*; D018408:Patch-Clamp Techniques / Q000379:methods; D020671:Posterior Horn Cells / Q000187:drug effects* / Q000502:physiology; D024642:Potassium Channels, Voltage-Gated / Q000502:physiology*; D051381:Rats; D015222:Sodium Channels / Q000502:physiology*; D013116:Spinal Cord / Q000166:cytology
chemical_list: D000778:Anesthetics, Dissociative; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels; D007649:Ketamine