Differential state-dependent Nav1.8 inhibition by suzetrigine, LTGO-33, and A-887826

Nav1.8 sodium channels are expressed in pain-sensing neurons, and some Nav1.8 inhibitors significantly reduce pain in clinical trials. Several Nav1.8 inhibitors have an unusual state dependence whereby inhibition is relieved by depolarization. We compared the state-dependent action of several Nav1.8 channel inhibitors to test whether inhibition is relieved during action potential (AP) firing under physiological conditions to produce "reverse use dependence." A-887826 inhibition was substantially relieved by AP waveforms applied at 20 Hz at 37°C. In contrast, there was no relief during AP trains with suzetrigine (VX-548) or LTGO-33, even though inhibition could be effectively removed by long, strong depolarizations. These differences were explained by differences in the voltage dependence and kinetics with which the compounds dissociate from depolarized channels and rebind to resting state channels. Suzetrigine required the strongest depolarizations for relief (midpoint +33 mV) and relief was slow (tau >300 ms at +20 mV), so almost no relief occurred during an AP waveform. Relief from A-887826 required weaker depolarizations (midpoint +13 mV) and was much faster, so some relief occurred during each AP waveform and accumulated during 20-Hz trains. LTGO-33 required the weakest depolarizations for relief (midpoint -11 mV) and relief was even faster than for A-887826, but reinhibition between AP waveforms was far faster than for A-887826, so that relief did not accumulate during AP trains at 20 Hz. The results show that, unlike A-887826, there is no use-dependent relief of inhibition by suzetrigine or LTGO-33 with physiological voltage waveforms at physiological temperatures, but each for different reasons.