INHIBITION OF BRAIN-CELL EXCITABILITY BY LIDOCAINE, QX314, AND TETRODOTOXIN - A MECHANISM FOR ANALGESIA FROM INFUSED LOCAL-ANESTHETICS

Local anesthetic infusions have been used to provide analgesia in a va riety of painful conditions. The mechanism for this drug effect remain s unknown. To better define the electrical effects of lidocaine concen trations comparable to those obtained during analgesic infusions, lido caine (0.05-3 mmol . l-1), QX314 (an obligatorily charged, quaternary lidocaine derivative applied within the cells), and tetrodotoxin (10 n mol . l-1) were applied to rat hippocampal pyramidal cells. The three drugs, which inhibit Na+ currents by varying mechanisms, produced toni c increases in (firing) current threshold, and decreases in the amplit ude of action potentials measured using an intracellular microelectrod e 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 f iring threshold by nearly 100%. Lidocaine 1-3 mmol . l-1 significantly inhibited action potential amplitude and increased threshold by as mu ch as 800%. Similarly, QX314 and tetrodotoxin produced greater increas es in current threshold than in action potential amplitude. QX314 prod uced 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 a nd more frequent stimulation to produce the phenomenon. Tetrodotoxin d emonstrated no phasic block. Increases in current threshold occurred i n lidocaine concentrations associated with analgesia and toxicity; inh ibition of action potentials occurred scarcely at all at these concent rations. Thus, tonic increases in current threshold may underlie analg esia and supplementation of general anesthesia by intravenous lidocain e.