Amitriptyline modulation of Na+ channels in rat dorsal root ganglion neurons

The effects of amitriptyline, a tricyclic antidepressant, on tetrodotoxin-s ensitive and tetrodotoxin-resistant Na+ currents in rat dorsal root ganglio n neurons were studied using the whole-cell patch damp method. Amitriptylin e blocked both types of Na+ currents in a dose-and holding potential-depend ent manner. At the holding potential of -80 mV, the apparent dissociation c onstants (K-d) for amitriptyline to block tetrodotoxin-sensitive and tetrod otoxin-resistant Na+ channels were 4.7 and 105 mu M, respectively. These va lues increased to 181 and 193 mu M, respectively, when the membrane was hel d at a potential negative enough to remove the steady-state inactivation. A mitriptyline dose-dependently shifted the steady-state inactivation curves in the hyperpolarizing direction and increased the values of the slope fact ors for both types of Na+ channels. The voltage dependence of the activatio n of both types of Na+ channels was shifted in the depolarizing direction. It was concluded that amitriptyline blocked the two types of Na+ channels i n rat sensory neurons by modulating the activation and the inactivation kin etics. (C) 2000 Elsevier Science B.V. All rights reserved.