Mechanism of inhibition by chlorpromazine of the human pain threshold sodium channel, Nav1.7

Chlorpromazine is a phenothiazine derivative which is primarily used for schizophrenia and occasionally for migraine. Because Na_v1.7 plays an important role in pain sensation, we investigated whether chlorpromazine blocks the human Na_v1.7 (hNa_v1.7) sodium current in HEK293 cells stably expressing hNa_v1.7 using the whole-cell patch-clamp technique. The peak current of hNa_v1.7 was reduced by chlorpromazine in a concentration-dependent manner with a half-maximal inhibitory concentration of 25.9±0.6μM and a Hill coefficient of 2.3±0.1. The Calmodulin inhibitory peptide did not abolish the blockade of hNa_v1.7 currents by chlorpromazine. The blockade of hNa_v1.7 currents by chlorpromazine was completely and repeatedly reversible after washout. The half-maximal voltage of activation of hNa_v1.7 was not changed by chlorpromazine. However, chlorpromazine caused hyperpolarized the steady-state inactivation of hNa_v1.7. The recovery from inactivation in the presence of chlorpromazine was slower than in the absence of chlorpromazine. Chlorpromazine also showed strong use-dependent inhibition of the hNa_v1.7 current. Our results demonstrate that chlorpromazine blocks the hNa_v1.7 current in concentration-, state- and use-dependent manners and suggest that it merits further study for potential use in pain management.