tetrodotoxin and Migraine-Disorders

Propranolol, a representative adrenergic β-receptor antagonist, is widely used to prevent migraine attacks. Although propranolol is well known to inhibit tetrodotoxin-resistant (TTX-R) Na

Topics: Animals; Electric Conductivity; Fluorescent Dyes; Ion Channel Gating; Male; Migraine Disorders; Neurons; Neurons, Afferent; Patch-Clamp Techniques; Propranolol; Rats, Sprague-Dawley; Sodium Channel Blockers; Sodium Channels; Tetrodotoxin

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

Approximately 20% of the adult population suffers from migraine. This debilitating pain disorder is three times more prevalent in women than in men. To begin to evaluate the underlying mechanisms that may contribute to this sex difference, we tested the hypothesis that there is a sex difference in the inflammatory mediator (IM)-induced sensitization of dural afferents. Acutely dissociated retrogradely labeled dural afferents from adult Sprague-Dawley rats were examined with whole cell patch-clamp recordings. Baseline passive and active electrophysiological properties of dural afferents from both sexes were comparable. However, while IM-induced increases in the excitability of dural afferents from male and female rats were also comparable, the proportion of dural afferents from female rats sensitized by IM (~100%) was significantly greater than that of dural afferents from male rats (~50%). This appeared to be due to differences downstream of IM receptors, as tetrodotoxin-resistant sodium current was increased by IM in a majority of male dural afferents (13/14). These data indicate that there are both quantitative and qualitative differences in the IM-induced sensitization of dural afferents that may contribute to the sex difference in the manifestation of migraine.

Topics: Action Potentials; Afferent Pathways; Animals; Blood Vessels; Bradykinin; Dinoprostone; Disease Models, Animal; Dura Mater; Electric Stimulation; Female; Histamine; Inflammation Mediators; Ion Channel Gating; Male; Migraine Disorders; Pain Perception; Patch-Clamp Techniques; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1D; Sensory Receptor Cells; Sex Characteristics; Sodium; Tetrodotoxin; Trigeminal Ganglion