Effects of ifenprodil on voltage-gated tetrodotoxin-resistant Na+ channels in rat sensory neurons

Background and objective: To examine a possible mechanism for the antinociceptive action of the N-methyl-D-aspartate receptor antagonist ifenprodil, we compared its effects with those of ketamine on tetrodotoxin-resistant Na channels in rat dorsal root ganglion neurons, which play an important role in the nociceptive pain pathway. Methods: Experiments were performed on dorsal root ganglion neurons from Sprague-Dawley rats, recordings of whole-cell membrane currents being made using patch-clamp technique. Results: Both drugs blocked tetroclotoxin-resistant Na+ currents dose dependently, their half-maximal inhibitory concentrations being 145 +/- 12.1 mu mol (ketamine) and 2.6 +/- 0.95 mu mol (ifenprodil). Ifenprodil shifted the inactivation curve for tetroclotoxin-resistant Na+ channels in the hyperpolarizing direction and shifted the activation curve in the depolarizing direction. Use-dependent blockade of tetroclotoxin-resistant Na+ channels was more marked with ifenprodil than with ketamine. When paired with lidocaine, these drugs produced similar additive inhibitions of tetrodotoxin-resistant Na+ channel activity. Conclusions: The observed suppressive effects on tetrodotoxin-resistant Na+ channel activity may, at least in part, underlie the antinociceptive effects of these N-methyl-D-aspartate receptor antagonists.