The Evidence for Effective Inhibition of I Na Produced by Mirogabalin ((1R,5S,6S)-6-(aminomethyl)-3-ethyl-bicyclo [3.2.0] hept-3-ene-6-acetic acid), a Known Blocker of Ca V Channels.

Mirogabalin (MGB, Tarlige ® ), an inhibitor of the α 2 δ-1 subunit of voltage-gated Ca 2+ (Ca V ) channels, is used as a way to alleviate peripheral neuropathic pain and diabetic neuropathy. However, to what extent MGB modifies the magnitude, gating, and/or hysteresis of various types of plasmalemmal ionic currents remains largely unexplored. In pituitary tumor (GH 3 ) cells, we found that MGB was effective at suppressing the peak (transient, I Na(T) ) and sustained (late, I Na(L) ) components of the voltage-gated Na + current ( I Na ) in a concentration-dependent manner, with an effective IC 50 of 19.5 and 7.3 μM, respectively, while the K D value calculated on the basis of minimum reaction scheme was 8.2 μM. The recovery of I Na(T) inactivation slowed in the presence of MGB, although the overall current-voltage relation of I Na(T) was unaltered; however, there was a leftward shift in the inactivation curve of the current. The magnitude of the window ( I Na(W) ) or resurgent I Na ( I Na(R) ) evoked by the respective ascending or descending ramp pulse (V ramp ) was reduced during cell exposure to MGB. MGB-induced attenuation in I Na(W) or I Na(R) was reversed by the further addition of tefluthrin, a pyrethroid insecticide known to stimulate I Na . MGB also effectively lessened the strength of voltage-dependent hysteresis of persistent I Na in response to the isosceles triangular V ramp . The cumulative inhibition of I Na(T), evoked by pulse train stimulation, was enhanced in its presence. Taken together, in addition to the inhibition of Ca V channels, the Na V channel attenuation produced by MGB might have an impact in its analgesic effects occurring in vivo.