The complex actions of sumatriptan on rat dural afferents.
OBJECTIVE
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-HT(1D) 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.


CONCLUSIONS
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.
University of Maryland, MD, USA.
Andrea M
AM
Harriott
Nicole N
NN
Scheff
Michael S
MS
Gold
D000818:Animals; D015220:Calcium Channels / Q000187:drug effects*; D004388:Dura Mater / Q000187:drug effects*; D005260:Female; D009475:Neurons, Afferent / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology*
D015220:Calcium Channels; D058825:Serotonin 5-HT1 Receptor Agonists; D018170:Sumatriptan