Sho‐Ya Wang, Joanna Calderon, Ging Kuo Wang
Sep 1, 2010
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Journal
Anesthesiology
Abstract
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 &mgr;m, respectively (mean ± SE, n = 5). The IC50 for the open Na+ channel was 0.25 ± 0.02 &mgr;m (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 &mgr;m; 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.