The effect of local anaesthetics on TTX-resistant sodium channels in sensory ganglia of the rat

Abstract

Local anaesthetics exert their effect by blocking the sodium channels in the peripheral nerve. In unmyelinated C-fibres however there is evidence that an additional type of sodium channel, the tetrodotoxin-resistant (TTX-R) Na+ channel [1] contributes to action potential propagation [2]. The different NA+ channels in different nerve fibres might be one explanation for differential nerve block induced by local anaesthetics. In this study the effects of local anaesthetics upon Dorsal Root Ganglia (DRG) TTX-R sodium channels were investigated. Table 11Table 11: (abstract 26). IC50-values for LA effect on TTX-resistant DRG sodium channels. Fitted values ± SEM. *IC50-values for C-fibre compound action potential block from [3]TTX-R Na+ currents of enzymatically dissociated adult rat DRG cells were investigated in 31 whole cell patches. The holding potential was set to − 100 mV and depolarizing pulses to −20 mV (5ms) were applied to elicit sodium currents. Experiments were carried out in 300 nM TTX-Ringer solution to block TTX-sensitive sodium currents. Local anaesthetics were applied externally. The temperature was 22°C in all experiments, external pH was adjusted to 7.4. A fitting method to assess phasic (use-dependent) block of sodium channels was developed. Concentration-inhibition curves for static block were derived for different local anaesthetics by quantifying for fractional peak sodium current block. Half-maximal inhibiting concentrations (IC50) were found by nonlinear least-squares fitting of the function B=c/(c + IC50) to data points and values are listed in the table. Results for the phasic block are not yet ready for publication in this abstract, but will be included in the presentation. This investigation gives a detailed study of local anaesthetic effects upon TTX-resistant sodium channels in mammalian sensory ganglia. Comparison of the TTX-R IC50 values with IC50 values for C-fibre block are surprisingly similar, whereas A fibres are already blocked at lower local anaesthetic concentrations [3]. Comparison of the observed effects with the effects upon TTX-sensitive channels of the same preparation (currently under investigation) should give more information about possible mechanisms of differential nerve block.