While blood vessels have long been implicated in diverse
pain syndromes (e.g.,
migraine headache,
angina pectoris,
vasculitis, and Raynaud's syndrome), underlying mechanisms remain to be elucidated. Recent evidence supports a contribution of the vascular endothelium in endothelin-1-induced
hyperalgesia, and its enhancement by repeated mechanical stimulation; a phenomenon referred to as stimulus-induced enhancement of (
endothelin)
hyperalgesia (SIEH). SIEH is thought to be mediated by release of
ATP from endothelial cells, to act on P2X3 receptors on nociceptors. In the present study we evaluated the ability of another vasoactive hyperalgesic agent,
epinephrine, to induce endothelial cell-dependent
hyperalgesia and SIEH. We found that
epinephrine also produces
hyperalgesia and SIEH. Both
P2X3 receptor antagonists,
A317491 and
octoxynol-9, which attenuate endothelial cell function, eliminated SIEH without affecting
epinephrine hyperalgesia. We further evaluated the hypothesis that members of two important classes of drugs used to treat
migraine headache, whose receptors are present in endothelial cells - the
triptans and β blockers - have a vascular component to their anti-hyperalgesic action. For this, we tested the effect of ICI-118,551, a β₂-
adrenergic receptor antagonist and
sumatriptan, an agonist at 5-HT1B and 5-HT₁D receptors, on nociceptive effects of
endothelin and
epinephrine. ICI-118,551 inhibited
endothelin SIEH, and attenuated
epinephrine hyperalgesia and SIEH.
Sumatriptan inhibited
epinephrine SIEH and inhibited
endothelin hyperalgesia and SIEH, while having no effect on
epinephrine hyperalgesia or the
hyperalgesia induced by a prototypical direct-acting inflammatory mediator,
prostaglandin E₂. These results support the suggestion that
triptans and β-blockers interact with the endothelial cell component of the blood vessel to produce anti-
hyperalgesia.