Journal
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
Volume 390, Issue 12, Pages 1255-1270Publisher
SPRINGER
DOI: 10.1007/s00210-017-1424-x
Keywords
Tricyclic antidepressants; Duloxetine; Voltage-gated sodium channels; Dorsal root ganglion
Categories
Funding
- Japan Society for the Promotion of Science [25462462]
- Grants-in-Aid for Scientific Research [25462462, 15K08686] Funding Source: KAKEN
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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 alpha 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 beta(1) subunit by using whole-cell, two-electrode, voltage clamp techniques. We also studied the role of the beta(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 alpha subunits with beta(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 beta(1) was most potent with a half-maximal inhibitory concentration (IC50) 4.6 mu mol/L. IC50 for amitriptyline on Na(v)1.3 coexpressed with beta(1) was lowered from 8.4 to 4.5 mu mol/L by coexpression with beta(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 alpha subunits. Moreover, the beta(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.
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