Sumatriptan Inhibits Neurogenic Vasodilation of Dural Blood Vessels in the Anaesthetized Rat—Intravital Microscope Studies

Abstract

This study used intravital microscopy to measure the diameter of dural arteries in anaesthetized rats. Electrical stimulation of the surface of a closed cranial window produced increases in dural vessel diameter which were blocked by the CGRP receptor antagonist human-alpha CGRP(8-37) but unaffected by the NK1 receptor antagonist RP67580. Sumatriptan (3 and 10 mg kg-1, i.v.) significantly reduced the response to electrical stimulation. In contrast, sumatriptan (3 mg kg-1) had no effects on the response to exogenously administered CGRP. These results indicate that neurokinins play no role in neurogenic vasodilation in this preparation and that neurogenic vasodilation in rat dural vessels is mediated predominantly by CGRP. Furthermore, the data indicate that sumatriptan attenuates neurogenic vasodilation, probably by inhibiting the release of CGRP from perivascular trigeminal nerve endings innervating the dura. These experimental data parallel the clinical findings that CGRP levels are elevated in migraine and normalized, concomitantly with headache relief, by sumatriptan.

The Role of Dopamine in a Model of Trigeminovascular Nociception

“…However, we have shown previously that the ␣ 2 -adrenoceptor is not involved in neurogenic dural vasodilation (Akerman et al, 2001). 5-HT 1B/1D receptors have been shown previously to inhibit the neurogenic response (Williamson et al, 1997b), the dose of yohimbine is not sufficient to inhibit these neurons. Yohimbine is able to actively inhibit ␣ 2 -adrenoceptor agonist effects at this dose (Hsu and Kakuk, 1984;Liu and Coupar, 1997).…”

“…Neurogenic dural vasodilation is thought to result from the presynaptic release of CGRP from trigeminal nerve terminals acting on CGRP receptors on the dural blood vessels, causing vasodilation (Williamson et al, 1997b). The data presented suggest that D 1 dopamine receptors may be involved in the control of the dural vasculature on trigeminal nerve endings.…”

“…Stimulation of dural sites is painful in humans (Ray and Wolff, 1940), and activation of trigeminal neurons in animal studies causes calcitonin gene-related peptide (CGRP) release (Goadsby et al, 1988) and dural blood vessel dilation (Williamson et al, 1997b). Both the CGRP release (Goadsby and Edvinsson, 1993) and dural blood vessel dilation (Williamson et al, 1997b) are inhibited by the triptans (5-HT 1B/1D receptor agonists), which are potent antimigraine compounds (Ferrari et al, 2001). Recent clinical trial evidence suggests that blockade of CGRP receptors has a potent acute antimigraine effect (Olesen et al, 2004).…”

“…Given the effects of dopamine on the cerebral, pial, and carotid arteries as well as the renal and mesenteric vasculature, we wanted to examine what effects dopamine might have on the dural vasculature and therefore whether it may be involved in any direct way in the headache phase of migraine. The intravital microscopy model of trigeminovascular activation uses the reaction of meningeal blood vessel caliber after electrical stimulation of a cranial window as a model of trigeminal nerve fiber activation (Williamson et al, 1997b), and it has proven to be an excellent model in predicting antimigraine efficacy (Williamson et al, 1997b). Previously, the triptans have been shown to attenuate neurogenic dural vasodilation (Williamson et al, 1997b).…”

“…The intravital microscopy model of trigeminovascular activation uses the reaction of meningeal blood vessel caliber after electrical stimulation of a cranial window as a model of trigeminal nerve fiber activation (Williamson et al, 1997b), and it has proven to be an excellent model in predicting antimigraine efficacy (Williamson et al, 1997b). Previously, the triptans have been shown to attenuate neurogenic dural vasodilation (Williamson et al, 1997b). We looked at the effects of dopamine agonists and antagonists on neurogenic dural vasodilation.…”