Complex Blockade of TTX-Resistant Na+ Currents by Lidocaine and Bupivacaine
Reduce Firing Frequency in DRG Neurons.
Andreas Scholz, Noboru Kuboyama , Gunter Hempelmann and Werner Vogel.
Physiologisches Institut, Justus-Liebig-Universitet Giessen, Aulweg 129, D-35392 Giessen, Germany.
APStracts 4:362N, 1997.
ABSTRACT
Mechanisms of blockade of tetrodotoxin-resistant (TTXr) Na+ channels by local
anesthetics in comparison to the sensitivity of tetrodotoxin-sensitive (TTXs)
Na+ channels were studied by means of the patch-clamp technique in neurons of
dorsal root ganglions (DRG) of rat. Half-maximum inhibitory concentration
(IC50) for the tonic block of TTXr Na+ currents by lidocaine was 210 (mol/l
whereas TTXs Na+ currents showed five times lower IC50 of 42 (mol/l.
Bupivacaine blocked TTXr and TTXs Na+ currents more potently with IC50 of 32
and 13 (mol/l, respectively. In the inactivated state, TTXr Na+ channel block
by lidocaine showed higher sensitivities (IC50 = 60 (mol/l) than in the
resting state underlying tonic blockade. The time constant (1 of recovery of
TTXr Na+ channels from inactivation at -80 mV was slowed from 2 ms to 5 ms
after addition of 10 (mol/l bupivacaine, whereas the (2 value of about 500 ms
remained unchanged. The use-dependent block of TTXr Na+ channels led to a
progressive reduction of current amplitudes with increasing frequency of
stimulation, which was up to 53% block at 20 Hz in 10 mol/l bupivacaine and
81% in 100 mol lidocaine. The functional importance of the use-dependent
block was confirmed in current-clamp experiments where 30 mol/l of lidocaine
or bupivacaine did not suppress the single action potential but clearly
reduced the firing frequency of action potentials again with stronger potency
of bupivacaine.
Since it was found that TTXr Na+ channels predominantly occur in smaller
sensory neurons their blockade might underlie the suppression of the sensation
of pain. Different sensitivities and varying proportions of TTXr and TTXs Na+
channels could explain the known differential block in spinal anesthesia. We
suggest that the frequency reduction at low local anesthetic concentrations
may explain the phenomenon of paresthesia where sensory information are
gradually suppressed during spinal anesthesia.
Received 22 September 1997; accepted in final form 2 December 1997.
APS Manuscript Number J780-7.
Article publication pending J. Neurophysiol.
ISSN 1080-4757 Copyright 1997 The American Physiological Society.
Published in APStracts on 12 December 1997