Pharmacological evidence that spinal alpha(2C)- and, to a lesser extent, alpha(2A)-adrenoceptors inhibit capsaicin-induced vasodilatation in the canine external carotid circulation

Villalon CM, Galicia-Carreon J, Gonzalez-Hernandez A, et al.

 Eur J Pharmacol 2012;683:204-210.

During a migraine attack capsaicin-sensitive trigeminal sensory nerves release calcitonin gene-related peptide (CGRP), producing cranial vasodilatation and central nociception; hence, trigeminal inhibition may prevent this vasodilatation and abort migraine headache. This study investigated the role of spinal alpha(2)-adrenoceptors and their subtypes (i.e. alpha(2A), alpha(2B) and/or alpha(2C)-adrenoceptors) in the inhibition of the canine external carotid vasodilator responses to capsaicin. Anaesthetized vagosympathectomized dogs were prepared to measure arterial blood pressure, heart rate and external carotid conductance. The thyroid artery was cannulated for one-min intracarotid infusions of capsaicin, alpha-CGRP and acetylcholine. A cannula was inserted intrathecally for spinal (C(1)-C(3)) administration of 2-amino-6-ethyl-4,5,7,8-tetrahydro-6H-oxazolo-[5,4-d]-azepin-dihydrochloride (B-HT 933; a selective alpha(2)-adrenoceptor agonist) and/or the alpha(2)-adrenoceptor antagonists rauwolscine (alpha(2A/2B/2C)), 2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408; alpha(2A)), imiloxan (alpha(2B)) or acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine (JP-1302; alpha(2C)). Infusions of capsaicin, alpha-CGRP and acetylcholine dose-dependently increased the external carotid conductance. Intrathecal B-HT 933 (1000 and 3100mug) inhibited the vasodilator responses to capsaicin, but not those to alpha-CGRP or acetylcholine. This inhibition, abolished by rauwolscine (310mug), was: (i) unaffected by 3100mug imiloxan; (ii) partially blocked by 310mug of BRL44408 or 100mug of JP-1302; and (iii) abolished by 1000mug of BRL44408 or 310mug of JP-1302. Thus, intrathecal B-HT 933 inhibited the external carotid vasodilator responses to capsaicin. This response, mediated by spinal alpha(2)-adrenoceptors unrelated to the alpha(2B)-adrenoceptor subtype, resembles the pharmacological profile of alpha(2C)-adrenoceptors and, to a lesser extent, alpha(2A)-adrenoceptors.