Inhibition of brain cell excitability by lidocaine, QX314, and tetrodotoxin: a mechanism for analgesia from infused local anesthetics?

Abstract

Local anesthetic infusions have been used to provide analgesia in a variety of painful conditions. The mechanism for this drug effect remains unknown. To better define the electrical effects of lidocaine concentrations comparable to those obtained during analgesic infusions, lidocaine (0.05-3 mmol.l-1), QX314 (an obligatorily charged, quaternary lidocaine derivative applied within the cells), and tetrodotoxin (10 mmol.l-1) were applied to rat hippocampal pyramidal cells. The three drugs, which inhibit Na+ currents by varying mechanisms, produced tonic increases in (firing) current threshold, and decreases in the amplitude of action potentials measured using an intracellular microelectrode technique. Lidocaine inhibited action potential spikes and increased current threshold in a concentration-dependent fashion. Lidocaine 50 and 100 mumol.l-1 did not inhibit action potentials, but increased firing threshold by nearly 100%. Lidocaine 1-3 mmol.l-1 significantly inhibited action potential amplitude and increased threshold by as much as 800%. Similarly, QX314 and tetrodotoxin produced greater increases in current threshold than in action potential amplitude. QX314 produced phasic (or frequency-dependent) block during trains of stimuli at 1 Hz, even when almost no tonic block was present. Lidocaine produced less phasic block than QX314, and required both greater tonic block and more frequent stimulation to produce the phenomenon. Tetrodotoxin demonstrated no phasic block. Increases in current threshold occurred in lidocaine concentrations associated with analgesia and toxicity; inhibition of action potentials occurred scarcely at all at these concentrations. Thus, tonic increases in current threshold may underlie analgesia and supplementation of general anesthesia by intravenous lidocaine.