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Mechanism of Action of Local Anesthetics on Synaptic Transmission in the Rat

Departments of Anesthesiology and Pharmacology, University of Pittsburgh School of Medicine, and VA Medical Center, Pittsburgh, Pennsylvania.

Abstract

The mechanism of action of local anesthetics on synaptic transmission and their effects on synaptic components and on electrophysiologic properties of the nerve cell body are not clear. Therefore, the effects of lidocaine and bupivacaine on pre- and postsynaptic mechanisms underlying synaptic transmission in sympathetic ganglia were studied utilizing the techniques of intracellular recording and stimulation on isolated superfused superior cervical ganglia of rats. Lidocaine and bupivacaine either depressed or completely blocked synaptic transmission in sympathetic ganglia in a dose-dependent manner. Blockade of axonal conduction in presynaptic fibers was preceded by increased latency (the latency increased from 11.2 ± 0.9 to 16.5 ± 1.4 ms, mean ± SEM, P < 0.01) when the drugs were applied to the presynaptic nerves. Application of the drugs directly to the ganglion produced alterations in postsynaptic membrane properties consisting of decreased membrane resistance (from 40 ± 3 to 32 ± 3 M, P < 0.01), increased firing threshold (from 14 ± 0.5 to 18 ± 0.5 mV, P < 0.01), and decreased action potential amplitude (P < 0.01) and/or blockade of action potential generation. Resting postsynaptic membrane potential did not change significantly. These changes were reversible. However, even after the excitatoy postsynaptic potential resulting from presynaptic nerve stimulation had fully recovered during washout of the local anesthetic, the threshold for evoking the spike potential (firing level) still remained elevated for both presynaptic and intracellular stimulation of the ganglion cell, suggesting prolonged cell depression. The decreased membrane resistance and prolonged depression of the ganglion cell outlasted the effects of the drugs on the preganglionic components by more than a factor of 2. The postganglionic compound action potential was depressed or abolished according to the anesthetic dose used. High frequency stimulation (5–15 Hz) of the preganglionic fibers caused significant reduction (P < 0.05) of the postganglionic compound action potential amplitude in the presence of the local anesthetics, suggesting possible depression of the synaptic processes such as transmitter release.

The results show that lidocaine and bupivacaine can produce reversible dose-dependent depression and/or blockade of synaptic transmission in the sympathetic ganglia of the rat by (a) blockade of axonal conduction in the presynaptic fibers; (b) depression of the postsynaptic cells; and (c) depression of the transmitter release. The prolonged action of the anesthetics on the postsynaptic cells suggests that sympathetic function may remain compromised well beyond the time necessary for the return of the axonal conduction. Lidocaine and bupivacaine produced similar effects even though in equimolar quantities the duration of action of bupivacaine was 2–3 times longer than that of lidocaine.

Key Words: ANESTHETICS, LOCAL-lidocaine, bupivacaine • SYMPATHETIC NERVOUS SYSTEM, SYNAPTIC TRANSMISSION-local anesthetic effects

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