Inhibition of Neuronal Na 1 Channels by Antidepressant Drugs 1

Although tricyclic antidepressant (TCA) blockade of cardiac Na channels is appreciated, actions on neuronal Na channels are less clear. Therefore, the effects of TCAs (amitriptyline, doxepin and desipramine) as well as trazadone and fluoxetine on voltage-gated Na current (INa) were examined in bovine adrenal chromaffin cells using the whole-cell patch-clamp method. Amitriptyline produced concentration-dependent depression of peak INa evoked from a holding potential of 280 mV with KD value of 20.2 mM and a Hill coefficient of 1.2. Although 20 mM amitriptyline induced no change in the rate or voltage dependence of INa activation, steady-state inactivation demonstrated a 15-mV hyperpolarizing shift. Similar results were observed for doxepin and desipramine. This shift in steady-state inactivation was associated with a slowed rate of recovery from the inactivated state. Contrasting results were observed with the atypical antidepressants: while 20 mM fluoxetine depressed peak INa by 61% and caused a 7-mV hyperpolarizing shift in steady-state inactivation, 100 mM trazodone decreased peak INa by only 19% and caused only a 3-mV shift. Although the magnitude of fluoxetine effects was similar to those of the TCAs, the onset of fluoxetine effects was substantially slower than for amitriptyline. In voltage-clamp and current-clamp measurements from neonatal rat dorsal root ganglion neurons, 20 mM amitriptyline decreased INa by 52% and depressed action potential dynamics consistent with enhanced Na channel inactivation. The effects of the TCAs on INa are similar to local anesthetic behavior and could contribute to certain analgesic actions. Although the primary mechanism by which TCAs relieve the symptoms of depressive illness appears to involve the inhibition of neurotransmitter reuptake, TCAs have additional effects on a variety of ion channels (Choi et al., 1992; Ogata et al., 1989; Schauf et al., 1975). For example, TCAs block Na channels in cardiac tissues in a fashion similar to the action of local anesthetics (Barber et al., 1991; Nattel, 1987), an effect that may contribute to their alteration in cardiac conduction and dysrhythmogenic actions. In addition to their antidepressant actions, TCAs have been known to exert an analgesic effect (Paoli et al., 1960) that is independent of the antidepressant action (Panerai et al., 1990). Acute administration of TCAs can exert an analgesic effect (Bromm et al., 1986; Coquoz et al., 1991; Poulsen et al., 1995), which may be useful in postoperative pain management (Tiengo et al., 1987). Long-term administration of the TCAs amitriptyline and desipramine diminishes pain in patients with diabetic neuropathy (Max et al., 1987, 1992) and other chronic pain conditions (Magni, 1991; Watson et al., 1982). Because the effects of TCAs on neuronal Na currents are less well described, we conducted a series of experiments to determine the sensitivity of neuronal Na channels to TCAs, and we compared their potency with that of the two atypical antidepressants, trazodone and fluoxetine, which differ greatly in analgesic potency. Bovine adrenal chromaffin cells, a wellcharacterized model for neuronal electrophysiology and secretion, were used to study the alteration of voltage-gated Na current (INa) and modulation of Na 1 channel inactivation by antidepressants. In addition, the use-dependent Na channel blockade by amitriptyline was characterized in isolated DRG neurons. A preliminary account of this work has been reported (Pancrazio et al., 1996).