Donitriptan, but not sumatriptan, inhibits capsaicin‐induced canine external carotid vasodilatation via 5‐HT_1B rather than 5‐HT_1D receptors

Abstract

Background and purpose: It has been suggested that during a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), resulting in cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the effects of the agonists sumatriptan (5-HT 1B/1D water-soluble), donitriptan (5-HT 1B/1D lipid-soluble), PNU-142633 (5-HT 1D water-soluble) and PNU-109291 (5-HT 1D lipid-soluble) on vasodilator responses to capsaicin, a-CGRP and acetylcholine in dog external carotid artery. Experimental approach: 59 vagosympathectomized dogs were anaesthetized with sodium pentobarbitone. Blood pressure and heart rate were recorded with a pressure transducer, connected to a cannula inserted into a femoral artery. A precalibrated flow probe was placed around the common carotid artery, with ligation of the internal carotid and occipital branches, and connected to an ultrasonic flowmeter. The thyroid artery was cannulated for infusion of agonists. Key results: Intracarotid infusions of capsaicin, a-CGRP and acetylcholine dose-dependently increased blood flow through the carotid artery. These responses remained unaffected after intravenous (i.v.) infusions of sumatriptan, PNU-142633, PNU-109291 or physiological saline; in contrast, donitriptan significantly attenuated the vasodilator responses to capsaicin, but not those to a-CGRP or acetylcholine. Only sumatriptan and donitriptan dose-dependently decreased the carotid blood flow. Interestingly, i.v. administration of the antagonist, SB224289 (5-HT 1B ), but not of BRL15572 (5-HT 1D ), abolished the inhibition by donitriptan. Conclusions and implications: Our results suggest that the inhibition produced by donitriptan of capsaicin-induced external carotid vasodilatation is mainly mediated by 5-HT 1B , rather than 5-HT 1D , receptors, probably by a central mechanism.

Enhanced pharmacological efficacy of sumatriptan due to modification of its physicochemical properties by inclusion in selected cyclodextrins

“…The anti-migraine properties of triptans may be due to vasoconstriction of the carotid arterial bed via 5-HT 1B receptors and the inhibition of CGRP release from trigeminal nerves via 5-HT 1B/D receptors, in our study sumatriptan forms were inactive in the capsaicin test. This lack of efficacy of sumatriptan in this test is, at least to some degree, in line with the results obtained by other authors who have shown that intravenous sumatriptan is not effective in the inhibition of capsaicin-induced responses related to cranial vasodilatation and central nociception 53 .…”

Inhibitory effect of chronic oral treatment with fluoxetine on capsaicin-induced external carotid vasodilatation in anaesthetised dogs

“…One-minute intracarotid continuous infusions of capsaicin, α-CGRP and acetylcholine induced dose-dependent increases in the external carotid blood flow (see Figures 2 and 3; control responses) without significant changes in mean blood pressure or heart rate (not shown), as previously reported (13,14,31). These vasodilator responses to capsaicin and α-CGRP were longer lasting (between five and 20 minutes) than those to acetylcholine (between one and five minutes).…”

“…After a stable haemodynamic condition for at least 60 minutes, baseline values of MAP, heart rate and external carotid blood flow were determined. Subsequently, all animals ( n = 48) received an intracarotid continuous infusion of phenylephrine (1.5 µg/min) to obtain a sustained carotid vasoconstriction, as previously reported (13,14). Twenty minutes later, all the different treatments were given without interrupting the infusion of phenylephrine.…”

“…The dose-intervals between the different doses of these compounds (given sequentially as they produced transient responses) ranged between five (acetylcholine) and 20 (capsaicin and α-CGRP) minutes, as in each case we waited until the external carotid blood flow had returned completely to baseline values. The doses of these compounds were selected from results previously published (13,14,31), in which dose-dependent increases in external carotid blood flow were elicited with no changes in arterial blood pressure or heart rate.…”

5‐HT1B receptors inhibit glutamate release from primary afferent terminals in rat medullary dorsal horn neurons

“…Similarly, sumatriptan, via the activation of 5‐HT 1D , rather than 5‐HT 1B , receptors has been shown to reduce glutamate release onto SG neurons of the Vc (Jennings et al ., 2004). Although these previous studies suggest that 5‐HT 1B receptors are not involved in the anti‐migraine action of triptans in trigeminovascular sensory neurons, recent studies have suggested that a central trigeminal action of triptans, which is mediated by 5‐HT 1B rather than 5‐HT 1D receptors could be involved in the processing of craniovascular pain (Muñoz‐Islas et al ., 2006; 2009). Further studies are needed to verify whether 5‐HT 1B receptors can inhibit glutamate release from trigeminovascular afferents onto Vc neurons.…”