Nitroglycerin (
glycerol trinitrate, GTN) induces
headache in migraineurs, an effect that has been used both diagnostically and in the study of the pathophysiology of this neurovascular
pain syndrome. An important feature of this
headache is a delay from the administration of GTN to
headache onset that, because of GTN's very rapid metabolism, cannot be due to its pharmacokinetic profile. It has recently been suggested that activation of perivascular mast cells, which has been implicated in the pathophysiology of
migraine, may contribute to this delay. We reported that
hyperalgesia induced by intradermal GTN has a delay to onset of ∼ 30 min in male and ∼ 45 min in female rats. This
hyperalgesia was greater in females, was prevented by pretreatment with the anti-
migraine drug,
sumatriptan, as well as by chronic pretreatment with the mast cell degranulator,
compound 48/80. The acute administration of GTN and
compound 48/80 both induced
hyperalgesia that was prevented by pretreatment with
octoxynol-9, which attenuates endothelial function, suggesting that GTN and mast cell-mediated
hyperalgesia are endothelial cell-dependent. Furthermore,
A-317491, a P2X3 antagonist, which inhibits endothelial cell-dependent
hyperalgesia, also prevents GTN and mast cell-mediated
hyperalgesia. We conclude that delayed-onset
mechanical hyperalgesia induced by GTN is mediated by activation of mast cells, which in turn release mediators that stimulate endothelial cells to release
ATP, to act on P2X3, a
ligand-gated ion channel, in perivascular nociceptors. A role of the mast and endothelial cell in GTN-induced
hyperalgesia suggests potential novel risk factors and targets for the treatment of
migraine.