Abstract
Duloxetine, an inhibitor of the serotonin-norepinephrine reuptake system, is widely used for the treatment of major depression and has also been found to be effective in reducing neuropathic pain. This latter effect is believed to be related to the role of the two neurotransmitters in inhibiting pain signals at the level of spinal and supraspinal neural circuits. However the possibility that duloxetine also acts through alternative mechanisms has not yet been investigated. In this study we focused on the potential effect of duloxetine on neuronal isoforms of voltage-gated sodium channels (NaV1.3 and NaV1.7) that have a pivotal role in the generation and propagation of pain signals. Conventional whole-cell patch-clamp recordings were performed on CHO-cells expressing hNaV1.3 and hNaV1.7. Duloxetine exerted a concentration-dependent resting block, measured by the reduction of the sodium current elicited by a single depolarizing step from -100mV to 0mV for 10 ms, with IC50 values of 5 and 16 microM for NaV1.3 and NaV1.7, respectively. These values were halved at holding potentials that reduce channel availability of both channels by 50%, indicating a preference for the inactivated state of sodium channels. Furthermore we observed that 10 microM duloxetine induced a 10mV negative shift of the steady state inactivation curves, and preliminary results indicate that this effect is correlated with stabilization of slow inactivation. Finally, for both sodium channel isoforms, an additional 20% inhibition over the resting block was observed at concentrations close to the IC50 when the stimulation frequency was increased up to 10Hz. Thus, the antidepressant duloxetine exhibits most of the state-dependent mechanisms of a classic sodium channel blocker. These results may add valuable information about the pharmacological spectrum of duloxetine, an issue of high clinical impact considering its increasingly widespread use.
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