Antidepressants inhibit Na v 1.3, Na v 1.7, and Na v 1.8 neuronal voltage-gated sodium channels more potently than Na v 1.2 and Na v 1.6 channels expressed in Xenopus oocytes.

Tricyclic antidepressants (TCAs) and duloxetine are used to treat neuropathic pain. However, the mechanisms underlying their analgesic effects remain unclear. Although many investigators have shown inhibitory effects of antidepressants on voltage-gated sodium channels (Nav ) as a possible mechanism of analgesia, to our knowledge, no one has compared effects on the diverse variety of sodium channel α subunits. We investigated the effects of antidepressants on sodium currents in Xenopus oocytes expressing Nav 1.2, Nav 1.3, Nav 1.6, Nav 1.7, and Nav 1.8 with a β1 subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the β3 subunit on the effect of antidepressants on Nav 1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with β1 . The inhibitory effects were more potent for Nav 1.3, Nav 1.7, and Nav 1.8, which are distributed in dorsal root ganglia, than Nav 1.2 and Nav 1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Nav 1.7 with β1 was most potent with a half-maximal inhibitory concentration (IC50 ) 4.6 μmol/L. IC50 for amitriptyline on Nav 1.3 coexpressed with β1 was lowered from 8.4 to 4.5 μmol/L by coexpression with β3 . Antidepressants predominantly inhibited the sodium channels expressed in dorsal root ganglia, and amitriptyline has the most potent inhibitory effect. This is the first evidence, to our knowledge, showing the diverse effects of antidepressants on various α subunits. Moreover, the β3 subunit appears important for inhibition of Nav 1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.