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.