Block of neuronal Na+ channels by antidepressant duloxetine in a state-dependent manner.
BACKGROUND
Duloxetine is a mixed serotonin-norepinephrine reuptake inhibitor used for major depressive disorder. Duloxetine is also beneficial for patients with diabetic peripheral neuropathy and with fibromyalgia, but how it works remains unclear.


METHODS
We used the whole cell, patch clamp technique to test whether duloxetine interacts with the neuronal Nav1.7 Na+ channel as a potential target. Resting and inactivated Nav1.7 Na+ channel block by duloxetine were measured by conventional pulse protocols in transfected human embryonic kidney cells. The open-channel block was determined directly using inactivation-deficient mutant Nav1.7 Na+ channels.


RESULTS
The 50% inhibitory concentration (IC50) of duloxetine for the resting and inactivated wild-type hNav1.7 Na+ channel were 22.1+/-0.4 and 1.79+/-0.10 microM, respectively (mean+/-SE, n=5). The IC50 for the open Na+ channel was 0.25+/-0.02 microM (n=5), as determined by the block of persistent late Nav1.7 Na+ currents. Similar open-channel block by duloxetine was found in the muscle Nav1.4 isoform (IC50=0.51+/-0.05 microM; n=5). Block by duloxetine appeared via the conserved local anesthetic receptor as determined by site-directed mutagenesis. Finally, duloxetine elicited strong use-dependent block of neuronal transient Nav1.7 Na+ currents during repetitive stimulations.


CONCLUSIONS
Duloxetine blocks persistent late Nav1.7 Na+ currents preferentially, which may in part account for its analgesic action.
Wang
Sho-Ya
SY
Department of Biology, State University of New York at Albany, Albany, New York, USA.
Calderon
Joanna
J
Kuo Wang
Ging
G
D000928:Antidepressive Agents / Q000494:pharmacology*; D002460:Cell Line; D000068736:Duloxetine Hydrochloride; D006801:Humans; D009154:Mutation / Q000235:genetics / Q000502:physiology; D062556:NAV1.7 Voltage-Gated Sodium Channel; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000235:genetics / Q000502:physiology*; D013876:Thiophenes / Q000494:pharmacology*
D000928:Antidepressive Agents; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride