Caramiphen-induced block of sodium currents and spinal anesthesia

The underlying mechanisms for the action of caramiphen used in local anesthesia are not well understood. The purpose of this study was to evaluate the block of caramiphen on voltage-gated Na+ channels and in spinal anesthesia. We investigated the effect of caramiphen on voltage-gated sodium channels in differentiated neuronal NG108-15 cells as well as on rat motor function, proprioception, and pain behavior (when administered intrathecally). In in vitro experiments, lidocaine produced concentration- and state-dependent effects on tonic block of voltage-gated Na+ currents (IC50 of 66.2 and 212.9 µM at holding potentials of −70 and −100 mV, respectively). Caramiphen exhibited a milder state-dependence of block (IC50 of 52.1 and 99.5 µM at holding potentials of −70 and −100 mV, respectively). Lidocaine showed a much stronger frequency-dependence of block than caramiphen: with high frequency stimulation (3.33 Hz), 50 µM caramiphen elicited an additional 20% blockade, whereas the same concentration of lidocaine produced 50% more block. In in vivo experiments, caramiphen with a more sensory-selective action over motor blockade was more potent than lidocaine (P<0.05) in spinal anesthesia. On an equipotent basis (25% effective dose (ED25), ED50, and ED75), the duration of caramiphen at producing spinal anesthesia was longer than that of lidocaine (P<0.01). Our data revealed that caramiphen had a more potent, prolonged spinal blockade with a more sensory/nociceptive-selective action over motor blockade in comparison with lidocaine. Spinal anesthesia with caramiphen could be through the suppression of voltage-gated Na+ currents.