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

摘要

Abstract 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 (Na v ) 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 Na v 1.2, Na v 1.3, Na v 1.6, Na v 1.7, and Na v 1.8 with a β 1 subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the β 3 subunit on the effect of antidepressants on Na v 1.3. All antidepressants inhibited sodium currents in an inactivated state induced by all five α subunits with β 1 . The inhibitory effects were more potent for Na v 1.3, Na v 1.7, and Na v 1.8, which are distributed in dorsal root ganglia, than Na v 1.2 and Na v 1.6, which are distributed primarily in the central nervous system. The effect of amitriptyline on Na v 1.7 with β 1 was most potent with a half-maximal inhibitory concentration (IC 50 ) 4.6?μmol/L. IC 50 for amitriptyline on Na v 1.3 coexpressed with β 1 was lowered from 8.4 to 4.5?μmol/L by coexpression with β 3 . 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 β 3 subunit appears important for inhibition of Na v 1.3. These findings may aid better understanding of the mechanisms underlying the pain relieving effects of antidepressants.