The complex actions of sumatriptan on rat dural afferents

Abstract

Aim To test the hypothesis that the clinical efficacy of triptans reflects convergent modulation of ion channels also involved in inflammatory mediator (IM)-induced sensitization of dural afferents. Methods Acutely dissociated retrogradely labeled rat dural afferents were studied with whole cell and perforated patch techniques in the absence and presence of sumatriptan and/or IM (prostaglandin E2, bradykinin, and histamine). Results Sumatriptan dose-dependently suppressed voltage-gated Ca2+ currents. Acute (2 min) sumatriptan application increased dural afferent excitability and occluded further IM-induced sensitization. In contrast, pre-incubation (30 min) with sumatriptan had no influence on dural afferent excitability and partially prevented IM-induced sensitization of dural afferents. The sumatriptan-induced suppression of voltage-gated Ca2+ currents and acute sensitization and pre-incubation-induced block of IM-induced sensitization were blocked by the 5-HT1D antagonist BRL 15572. Pre-incubation with sumatriptan failed to suppress the IM-induced decrease in action potential threshold and overshoot (which results from modulation of voltage-gated Na+ currents) and activation of Cl− current, and had no influence on the Cl− reversal potential. However, pre-incubation with sumatriptan caused a dramatic hyperpolarizing shift in the voltage dependence of K+ current activation. Discussion These results indicate that although the actions of sumatriptan on dural afferents are complex, at least two distinct mechanisms underlie the antinociceptive actions of this compound. One of these mechanisms, the shift in the voltage dependence of K+ channel activation, may suggest a novel strategy for future development of anti-migraine agents.