Effect of amitriptyline on tetrodotoxin-resistant Na(v)1.9 currents in nociceptive trigeminal neurons

BACKGROUND: Amitriptyline (AMI) is tricyclic antidepressant that has been widely used to manage various chronic pains such as migraines. Its efficacy is attributed to its blockade of voltage-gated sodium channels (VGSCs). However, the effects of AMI on the tetrodotoxin-resistant (TTX-r) sodium channel Na(v)1.9 currents have been unclear to present. RESULTS: Using a whole-cell patch clamp technique, this study showed that AMI efficiently inhibited Na(v)1.9 currents in a concentration-dependent manner and had an IC(50) of 15.16 μM in acute isolated trigeminal ganglion (TG) neurons of the rats. 10 μM AMI significantly shifted the steady-state inactivation of Na(v)1.9 channels in the hyperpolarizing direction without affecting voltage-dependent activation. Surprisingly, neither 10 nor 50 μM AMI caused a use-dependent blockade of Na(v)1.9 currents elicited by 60 pulses at 1 Hz. CONCLUSION: These data suggest that AMI is a state-selective blocker of Na(v)1.9 channels in rat nociceptive trigeminal neurons, which likely contributes to the efficacy of AMI in treating various pains, including migraines.