High systemic lidocaine concentrations exert well-known toxic effects on the central nervous system (CNS), including seizures, coma, and death. The underlying mechanisms are still largely obscure, and the actions of lidocaine on supraspinal neurons have received comparatively little study. We recently found that lidocaine at clinically neurotoxic concentrations increases excitability mediated by Na+-independent, high-threshold (HT) action potential spikes in rat thalamocortical neurons. Our goal in this study was to characterize these spikes and test the hypothesis that they are generated by HT Ca2+ currents, previously implicated in neurotoxicity. We also sought to identify and isolate the specific underlying subtype of Ca2+ current.
We investigated the actions of lidocaine in the CNS-toxic concentration range (100 μM–1 mM) on ventrobasal thalamocortical neurons in rat brain slices in vitro, using whole-cell patch-clamp recordings aided by differential interference contrast infrared videomicroscopy. Drugs were bath applied; action potentials were generated using current clamp protocols, and underlying currents were identified and isolated with ion channel blockers and electrolyte substitution.
Lidocaine (100 μM–1 mM) abolished Na+-dependent tonic firing in all neurons tested (n = 46). However, in 39 of 46 (85%) neurons, lidocaine unmasked evoked HT action potentials with lower amplitudes and rates of de-/repolarization compared with control. These HT action potentials remained during the application of tetrodotoxin (600 nM), were blocked by Cd2+ (50 μM), and disappeared after superfusion with an extracellular solution deprived of Ca2+. These features implied that the unmasked potentials were generated by high-voltage–activated Ca2+ channels and not by Na+ channels. Application of the L-type Ca2+ channel blocker, nifedipine (5 μM), completely blocked the HT potentials, whereas the N-type Ca2+ channel blocker, ω-conotoxin GVIA (1 μM), had little effect.
At clinically CNS-toxic concentrations, lidocaine unmasked in thalamocortical neurons evoked HT action potentials mediated by the L-type Ca2+ current while substantially suppressing Na+-dependent excitability. On the basis of the known role of an increase in intracellular Ca2+ in the pathogenesis of local anesthetic neurotoxicity, this novel action represents a plausible contributing candidate mechanism for lidocaine’s CNS toxicity in vivo.
Published ahead of print January 14, 2016
From the *Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada; and †Department of Anesthesia, St. Paul’s Hospital, Vancouver, British Columbia, Canada.
Amer A. Ghavanini, MD, PhD, FRCPC, is currently affiliated with the Division of Neurology, University of Toronto, Ontario, Canada; and Trillium Health Partners, Mississauga, Ontario, Canada.
Katrin S. Meyer Schöniger, MD, is currently affiliated with the Klinik für Anästhesie, Chirurgische Intensivmedizin, Rettungsmedizin und Schmerztherapie [KLIFAIRS], Luzerner Kantonsspital, Luzern, Switzerland.
Accepted for publication December 3, 2015.
Published ahead of print January 14, 2016
Funding: Supported in part by the Canadian Anesthesia Research Foundation through a Canadian Anesthesiologists’ Society Research Award and a Canadian Anesthesiologists’ Society/Abbott Laboratories Ltd. Career Scientist Award in Anesthesia (Toronto, Ontario, Canada); the Canada Foundation for Innovation (Ottawa, Ontario, Canada); the British Columbia Knowledge Development Fund (Victoria, British Columbia, Canada); a Pfizer Neuropathic Pain Research Award (independently peer-reviewed public operating grant competition sponsored by Pfizer Canada Inc.; Kirkland, Quebec, Canada); and the St. Paul’s Hospital Department of Anesthesia (Vancouver, British Columbia, Canada). Dr. Schwarz holds the Dr. Jean Templeton Hugill Chair in Anesthesia, supported by the Dr. Jean Templeton Hugill Endowment for Anesthesia Memorial Fund.
The authors declare no conflicts of interest.
Reprints will not be available from the authors.
Address correspondence to Stephan K. W. Schwarz, MD, PhD, FRCPC, Department of Anesthesiology, Pharmacology & Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, BC, Canada V6T 1Z3. Address e-mail to firstname.lastname@example.org.