COMPLEX BLOCKADE OF TTX-RESISTANT NA+ CURRENTS BY LIDOCAINE AND BUPIVACAINE REDUCE FIRING FREQUENCY IN DRG NEURONS

Mechanisms of blockade of tetrodotoxin-resistant (TTXr) Na+ channels b y local anesthetics in comparison with the sensitivity of tetrodotoxin -sensitive (TTXs) Na+ channels were studied by means of the patch-clam p technique in neurons of dorsal root ganglions (DRG) of rat. Half-max imum inhibitory concentration (IC50) for the tonic block of TTXr Na+ c urrents by lidocaine was 210 mu mol/l, whereas TTXs Na+ currents showe d five times lower IC50 Of 42 mu mol/l. Bupivacaine blocked TTXr and T TXs Na+ currents more potently with IC50 of 32 and 13 mu mol/l, respec tively. In the inactivated state, TTXr Na+ channel block by lidocaine showed higher sensitivities (IC50 = 60 mu mol/l) than in the resting s tate underlying tonic blockade. The time constant tau(1) of recovery o f TTXr Na+ channels from inactivation at -80 mV was slowed from 2 to 5 ms after addition of 10 mu mol/l bupivacaine, whereas the tau(2) valu e of similar to 500 ms remained unchanged. The use-dependent block of TTXr Nat channels led to a progressive reduction of current amplitudes with increasing frequency of stimulation, which was less than or equa l to 53% block at 20 Hz in 10 mu mol/l bupivacaine and 81% in 100 mu m ol lidocaine. The functional importance of the use-dependent block was confirmed in current-clamp experiments where 30 mu mol/l of lidocaine or bupivacaine did not suppress the single action potential but clear ly reduced the firing frequency of action potentials again with strong er potency of bupivacaine. Because 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 sensitivi ties and varying proportions of TTXr and TTXs Na+ channels could expla in the known differential block in spinal anesthesia. We suggest that the frequency reduction at low local anesthetic concentrations may exp lain the phenomenon of paresthesia where sensory information are suppr essed gradually during spinal anesthesia.