Lidocaine blocks the hyperpolarization-activated mixed cation current, ih, in rat thalamocortical neurons
Background: The mechanisms that underlie the supraspinal central nervous system effects of systemic lidocaine are poorly understood and not solely explained by Na+ channel blockade. Among other potential targets is the hyperpolarization-activated cation current, Ih, which is blocked by lidocaine in peripheral neurons. Ih is highly expressed in the thalamus, a brain area previously implicated in lidocaine's systemic effects. The authors tested the hypothesis that lidocaine blocks Ih in rat thalamocortical neurons. Methods: The authors conducted whole cell voltage-and current-clamp recordings in ventrobasal thalamocortical neurons in rat brain slices in vitro. Drugs were bath-applied. Data were analyzed with Student t tests and ANOVA as appropriate; α = 0.05. Results: Lidocaine voltage-independently blocked Ih, with high efficacy and a half-maximal inhibitory concentration (IC50) of 72 μM. Lidocaine did not affect Ih activation kinetics but delayed deactivation. The Ih inhibition was accompanied by an increase in input resistance and membrane hyperpolarization (maximum, 8 mV). Lidocaine increased the latency of rebound low-threshold Ca2+ spike bursts and reduced the number of action potentials in bursts. At depolarized potentials associated with the relay firing mode (&gt;-60 mV), lidocaine at 600 μM concurrently inhibited a K conductance, resulting in depolarization (7-10 mV) and an increase in excitability mediated by Na+-independent, high-threshold spikes. Conclusions: Lidocaine concentration-dependently inhibited Ih in thalamocortical neurons in vitro, with high efficacy and a potency similar to Na+ channel blockade. This effect would reduce the neurons' ability to produce intrinsic burst firing and δ rhythms and thereby contribute to the alterations in oscillatory cerebral activity produced by systemic lidocaine in vivo. © 2011, the American Society of Anesthesiologists, Inc. Lippincott Williams &amp; Wilkins. Anesthesiology.