Dilatation induced by 5-HT in the middle meningeal artery of the anaesthetised cat.

In chloralose-anaesthetised cats, we studied the effects of intravenous and intra-carotid injections of 5-HT on the middle meningeal artery and the way these were modified by 5-HT antagonists. Cats were prepared for blood pressure recording and intravenous injections and a catheter inserted into one carotid artery via a lingual artery. The middle meningeal arteries were exposed and blood flow recorded with laser Doppler probes. Intravenous injections of 5-HT, 2-50 microg kg(-1) (5.2-129 nmole kg(-1)), produced a dose-dependent fall in blood pressure, a rise in meningeal blood flow, and an associated fall in middle meningeal resistance. Resistance changes were the result of a local dilatation and not due to changes downstream of the recording probe. Intracarotid injections of 5-HT produced similar systemic and craniovascular responses, which were larger in the ipsilateral middle meningeal artery. Dose-response curves of vascular resistance changes to intravenous injection of 5-HT were not significantly affected by WAY100635 (5-HT1A antagonist), GR127935 (5-HT(1B/1D) antagonist), methiothepin (5-HT2C and 5-HT7 antagonist), ketanserin (5-HT2A antagonist), SB203186 (5-HT4 antagonist) or cervical sympathectomy, but were blocked by the 5-HT(3/4) antagonist tropisetron, the 5-HT3 antagonist ondansetron, the ganglion-blocking drug hexamethonium and by vagotomy. These drugs and procedures did not significantly antagonise the response to intra-arterially injected 5-HT. We conclude that intravenously-administered 5-HT is a vasodilator in vivo in the cat dural circulation, and that the dilation is not mediated by 5-HT1, 5-HT2, 5-HT4 or 5-HT7 receptors, but is primarily mediated by a vagal reflex, initiated via 5-HT3 receptor activation and brought about by an increase in parasympathetic tone to the middle meningeal artery as part of the von Bezold-Jarisch reflex. There also appears to be a direct vasodilator effect mediated by unknown receptor types, particularly after intra-arterial administration. Neither of these effects is, however, likely to be of importance in the pathophysiology of migraine or other vascular headaches.

The role of 5-HT1B and 5-HT1D receptors in the selective inhibitory effect of naratriptan on trigeminovascular neurons.

The importance of 5-HT(1B) and 5-HT(1D) receptors in the actions of the anti-migraine drug naratriptan was investigated using the relatively selective 5-HT(1) receptor ligands SB224289 and BRL15572. Electrical stimulation of the superior sagittal sinus (SSS) in cats activated neurones in the trigeminal nucleus caudalis. Facial receptive fields (RF) were also electrically stimulated to activate the same neurones. Responses of these neurones to SSS stimulation were suppressed by iontophoretic application of naratriptan (5-50 nA). There were two distinct populations of neurones in the nucleus--those in deeper laminae in which the responses to SSS and RF stimulation were equally suppressed by naratriptan ('non-selective') and more superficial neurones in which only the SSS responses were suppressed by naratriptan ('selective'). Concurrent micro-iontophoretic application (50 nA) of the 5-HT(1D) antagonist BRL15572 antagonised the suppression by naratriptan of the response of 'selective' cells to SSS stimulation. Iontophoretic application of SB224289 (50 nA), a 5-HT(1B) antagonist, antagonised the suppression by naratriptan of responses of 'non-selective' cells to RF stimulation and, to a lesser extent, also antagonised the suppression of responses to SSS stimulation. Intravenous administration of SB224289 antagonised the suppression only of RF responses of "non-selective" neurons by naratriptan and intravenous administration of BRL15572 antagonised the suppression only of SSS responses of "selective" neurons by naratriptan. These results suggest that the response of nucleus caudalis neurons to stimulation of the sagittal sinus can be modulated by both 5-HT(1B) and 5-HT(1D) receptor activation, with the 5-HT(1D) receptors perhaps playing a greater role. The response to RF stimulation is more influenced by 5-HT(1B) receptor modulation with 5-HT(1D) receptors being less important. Therefore, this suggests that selective 5-HT(1D) agonists may be able to target the neuronal population, which is selectively involved in the transmission of dural inputs. We conclude that the central terminals of trigeminal primary afferent fibres contain 5-HT(1B) and 5-HT(1D) receptors. Primary afferents from the dura mater may predominantly express 5-HT(1D) receptors, while facial afferents may predominantly express 5-HT(1B) receptors. Activation of 5-HT(1D) receptors in particular may be important in the anti-migraine effect of naratriptan.