Thomas Stoehr

Differential Block of Sensory Neuronal Voltage-Gated Sodium Channels by Lacosamide [(2R)-2-(Acetylamino)-N-benzyl-3-methoxypropanamide], Lidocaine, and Carbamazepine

Voltage-gated sodium channels play a critical role in excitability of nociceptors (pain-sensing neurons). Several different sodium channels are thought to be potential targets for pain therapeutics, including Nav1.7, which is highly expressed in nociceptors and plays crucial roles in human pain and hereditary painful neuropathies, Nav1.3, which is up-regulated in sensory neurons following chronic inflammation and nerve injury, and Nav1.8, which has been implicated in inflammatory and neuropathic pain mechanisms. We compared the effects of lacosamide [(2R)-2-(acetylamino)-N-benzyl-3-methoxypropanamide], a new pain therapeutic, with those of lidocaine and carbamazepine on recombinant Nav1.7 and Nav1.3 currents and neuronal tetrodotoxin-resistant (Nav1.8-type) sodium currents using whole-cell patch-clamp electrophysiology. Lacosamide is able to substantially reduce all three current types. However, in contrast to lidocaine and carbamazepine, 1 mM lacosamide did not alter steady-state fast inactivation. Inhibition by lacosamide exhibited substantially slower kinetics, consistent with the proposal that lacosamide interacts with slow-inactivated sodium channels. The estimated IC50 values for inhibition by lacosamide of Nav1.7-, Nav1.3-, and Nav1.8-type channels following prolonged inactivation were 182, 415, and 16 μM, respectively. Nav1.7-, Nav1.3-, and Nav1.8-type channels in the resting state were 221-, 123-, and 257-fold less sensitive, respectively, to lacosamide than inactivated channels. Interestingly, the ratios of resting to inactivated IC50s for carbamazepine and lidocaine were much smaller (ranging from 3 to 16). This suggests that lacosamide should be more effective than carbamazepine and lidocaine at selectively blocking the electrical activity of neurons that are chronically depolarized compared with those at more normal resting potentials.