a-803467 and Migraine-Disorders

Amitriptyline (AMI), a tricyclic antidepressant, has been widely used to prevent migraine attacks and alleviate other various chronic pain, but the underlying mechanism remains unclear. Accumulated evidence suggests that the efficacy of AMI is related to the blockade of voltage-gated sodium channels. The aim of the present study was to investigate the effect of AMI on Na(v)1.8 currents in nociceptive trigeminal neurons and trigeminovascular nociception induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus (SSS) in rats, as in the animal model of vascular headaches such as migraines. Using a whole-cell voltage recording technique, we showed that Na(v)1.8 currents were blocked by AMI in a concentration-dependent manner, with an IC50 value of 6.82 μM in acute isolated trigeminal ganglion neurons of the rats. AMI caused a hyperpolarizing shift in the voltage-dependent activation and steady-state inactivation and significantly blocked in a use-dependent manner and slowed the recovery from the inactivation of Na(v)1.8 currents. In addition, the systemic administration of AMI and A-803467 (a selective Na(v)1.8 channel blocker) potently alleviated the nociceptive behaviors (head flicks and grooming) induced by the electrical stimulation of the dura mater surrounding the SSS. Taken together, our data suggest that Na(v)1.8 currents in nociceptive trigeminal neurons are blocked by AMI through modulating the activation and inactivation kinetics, which may contribute to anti-nociceptive effect of AMI in animal models of migraines.

Topics: Afferent Pathways; Amitriptyline; Aniline Compounds; Animals; Blood Vessels; Disease Models, Animal; Dose-Response Relationship, Drug; Dura Mater; Electric Stimulation; Furans; Ion Channel Gating; Male; Migraine Disorders; NAV1.8 Voltage-Gated Sodium Channel; Nociception; Nociceptors; Rats; Rats, Sprague-Dawley; Single-Blind Method; Sodium; Sodium Channel Blockers; Superior Sagittal Sinus; Tetrodotoxin; Trigeminal Nerve