Migraine treatment has evolved into the scientific arena, but it seems still controversial whether migraine is primarily a vascular or a neurological dysfunction. Irrespective of this controversy, the levels of serotonin (5-hydroxytryptamine; 5-HT), a vasoconstrictor and a central neurotransmitter, seem to decrease during migraine (with associated carotid vasodilatation) whereas an i.v. infusion of 5-HT can abort migraine. In fact, 5-HT as well as ergotamine, dihydroergotamine and other antimigraine agents invariably produce vasoconstriction in the external carotid circulation. The last decade has witnessed the advent of sumatriptan and second generation triptans (e.g. zolmitriptan, rizatriptan, naratriptan), which belong to a new class of drugs, the 5-HT1B/1D/1F receptor agonists. Compared to sumatriptan, the second-generation triptans have a higher oral bioavailability and longer plasma half-life. In line with the vascular and neurogenic theories of migraine, all triptans produce selective carotid vasoconstriction (via 5-HT1B receptors) and presynaptic inhibition of the trigeminovascular inflammatory responses implicated in migraine (via 5-HT1D/5-ht1F receptors). Moreover, selective agonists at 5-HT1D (PNU-142633) and 5-ht1F (LY344864) receptors inhibit the trigeminovascular system without producing vasoconstriction. Nevertheless, PNU-142633 proved to be ineffective in the acute treatment of migraine, whilst LY344864 did show some efficacy when used in doses which interact with 5-HT1B receptors. Finally, although the triptans are effective antimigraine agents producing selective cranial vasoconstriction, efforts are being made to develop other effective antimigraine alternatives acting via the direct blockade of vasodilator mechanisms (e.g. antagonists at CGRP receptors, antagonists at 5-HT7 receptors, inhibitors of nitric oxide biosynthesis, etc). These alternatives will hopefully lead to fewer side effects.
1 It has recently been shown that both a 1 -and a 2 -adrenoceptors mediate vasoconstriction in the canine external carotid circulation. The present study set out to identify the speci®c subtypes (a 1A , a 1B and a 1D as well as a 2A , a 2B and a 2C ) mediating the above response. 2 Consecutive 1 min intracarotid infusions of phenylephrine (a 1 -adrenoceptor agonist) and BHT933 (a 2 -adrenoceptor agonist) produced dose-dependent decreases in external carotid blood ow, without aecting mean arterial blood pressure or heart rate. 3 The responses to phenylephrine were selectively antagonized by the antagonists, 5-methylurapidil (a 1A ) or BMY7378 (a 1D ), but not by L-765,314 (a 1B ), BRL44408 (a 2A ), imiloxan (a 2B ) or MK912 (a 2C ). In contrast, only BRL44408 or MK912 aected the responses to BHT933. 4 The above results support our contention that mainly the a 1A , a 1D , a 2A and a 2C -adrenoceptor subtypes mediate vasoconstriction in the canine external carotid circulation.
Even though the underlying mechanisms for the pathophysiology of migraine attacks are not completely understood, little doubt exists that the headache phase is explained by dilatation of cranial, extracerebral blood vessels. In this context, experimental models predictive for anti‐migraine activity have shown that both triptans and ergot alkaloids, which abort migraine headache, produce vasoconstriction within the carotid circulation of different species. In contrast to the well‐established role of serotonin (5‐hydroxytryptamine; 5‐HT) 5‐HT1B receptors in the common carotid vascular bed, the role of α‐adrenoceptors and their subtypes has been examined only relatively recently. Using experimental animal models and α1‐ and α2‐adrenoceptor agonists (phenylephrine and BHT933, respectively) and antagonists (prazosin and rauwolscine, respectively), it was shown that activation of either receptor produces a cranioselective vasoconstriction. Subsequently, investigations employing relatively selective antagonists at α1‐ (α1A, α1B, α1D) and α2‐ (α2A, α2B, α2C) adrenoceptor subtypes revealed that specific receptors mediate the carotid haemodynamic responses in these animals. From these observations, together with the potential limited role of α1B‐ and α2C‐adrenoceptors in the regulation of systemic haemodynamic responses, it is suggested that selective agonists at these receptors may provide a promising novel avenue for the development of acute anti‐migraine drugs.
The present study set out to investigate the external carotid vascular effects of isometheptene in vagosympathectomised dogs, anaesthetised with pentobarbital. One-minute intracarotid (intra-arterial; i.a.) infusions of isometheptene (10, 30, 100 and 300 microg/min) produced dose-dependent decreases in external carotid blood flow, without affecting blood pressure or heart rate. The vasoconstrictor responses to 100 microg/min and 300 microg/min of isometheptene were clearly attenuated in animals pretreated with reserpine (5,000 microg/kg). Moreover, after prazosin (an alpha1-adrenoceptor antagonist; 100 microg/kg), the responses to isometheptene remained unaltered in untreated as well as reserpine-pretreated dogs. In contrast, the responses to isometheptene were attenuated by rauwolscine (an alpha2-adrenoceptor antagonist; 300 microg/kg) in untreated animals, and were practically abolished in reserpine-pretreated dogs. Further investigation into the specific alpha2-adrenoceptor subtypes, using selective antagonists, showed that BRL44408 (alpha2A) and MK912 (alpha2C) markedly attenuated this response, while imiloxan (alpha2B) was ineffective. The involvement of 5-HT1B and 5-HT1D receptors seems highly unlikely since antagonists at 5-HT1B (SB224289) and 5-HT1D (BRL15572) receptors (both at 300 microg/kg) were ineffective. On this basis, it is concluded that isometheptene-induced canine external carotid vasoconstriction is mediated by both indirect (a tyramine-like action) and direct (acting at receptors) mechanisms, which mainly involve alphaA- and alpha2C-adrenoceptors, while the involvement of alpha1-adrenoceptors seems rather limited.
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