Mechanism of inhibition by chlorpromazine of the human pain threshold sodium channel, Na v 1.7.

Chlorpromazine is a phenothiazine derivative which is primarily used for schizophrenia and occasionally for migraine. Because Nav 1.7 plays an important role in pain sensation, we investigated whether chlorpromazine blocks the human Nav 1.7 (hNav 1.7) sodium current in HEK293 cells stably expressing hNav 1.7 using the whole-cell patch-clamp technique. The peak current of hNav 1.7 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 hNav 1.7 currents by chlorpromazine. The blockade of hNav 1.7 currents by chlorpromazine was completely and repeatedly reversible after washout. The half-maximal voltage of activation of hNav 1.7 was not changed by chlorpromazine. However, chlorpromazine caused hyperpolarized the steady-state inactivation of hNav 1.7. 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 hNav 1.7 current. Our results demonstrate that chlorpromazine blocks the hNav 1.7 current in concentration-, state- and use-dependent manners and suggest that it merits further study for potential use in pain management.