Possible Role of α-Adrenoceptor Subtypes in Acute Migraine Therapy

Abstract

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.

Pharmacological Characterization of a Novel α2C-Adrenoceptor AgonistN-[3,4-dihydro-4-(1H-imidazol-4-ylmethyl)-2H-1, 4-benzoxazin-6-yl]-N-ethyl-N′-methylurea (Compound A)

“…In addition to a therapeutic use in nasal congestion, compound A provides a powerful tool to explore the various physiological roles of peripheral ␣ 2C -adrenoceptors. ␣ 2C -Adrenoceptor agonists might be potentially attractive targets for a variety of conditions such as migraine (Willems et al, 2003), chronic heart failure (Brede et al, 2002), neuropathic pain (Graham et al, 2000), and schizophrenia (Sallinen et al, 1998). New selective ␣ 2C -adrenoceptor drugs may therefore represent novel therapeutic strategy in the treatment of these diseases.…”

“…Therefore, a strong need exists to develop subtype-selective ␣ 2 -adrenoceptor compounds to identify the pharmacological properties attributable to each specific ␣ 2 -adrenoceptor subtype. Among the ␣ 2 -adrenoceptor subtypes, it has been suggested that the ␣ 2C -adrenoceptor was implicated as a potential target for the treatment of nasal congestion (Stafford-Smith et al, 2007) and other indications such as migraine (Willems et al, 2003), chronic heart failure (Brede et al, 2002), neuropathic pain (Graham et al, 2000), and schizophrenia (Sallinen et al, 1998). However, because of the lack of ligands that recognize only the ␣ 2C -adrenoceptor subtype, studies on the distribution and the physiological relevance of this subtype and their therapeutics have been limited.…”

Effect of some acute and prophylactic antimigraine drugs on the vasodepressor sensory CGRPergic outflow in pithed rats

“…In this respect, the acute antimigraine drugs sumatriptan, dihydroergotamine and ergotamine have been reported to produce cranial vasoconstriction by activation of, respectively: (i) 5-HT 1B receptors ; (ii) 5-HT 1B and α 2A/2C -adrenoceptors ; and (iii) 5-HT 1B , α 2A/2C -and, to a lesser extent, α 1 -adrenoceptors . Moreover, stimulation of α 1 /α 2 -adrenoceptors, 5-HT 2 and, to a much lesser extent, 5-HT 1B receptors in the systemic vasculature produces vasoconstriction and vasopressor responses (see Villalón and Centurión, 2007;Willems et al, 2003).…”

α2-Adrenergic receptor signalling in hypertension

“…Clinical studies in Raynaud's patients have also documented a significant role for α 2 -ARs in the exaggerated cold-induced vasoconstriction typical of this syndrome [40,43,44], although there are other reports that α 2 -AR blockade has little or no effect on cold-induced vasoconstriction [45][46][47]. In addition, the α 2C -ARs appear to contribute to cerebral blood flow by regulating tone in the carotid artery [48,49], and recent studies suggest subtype selective activation of these receptors causes vasoconstriction which may be a beneficial therapy for migraine [38,49]. Thus α 2C -ARs may play a unique and very selective role in thermoregulation.…”