Clonidine inhibits the canine external carotid vasodilatation to capsaicin by alpha2A/2C-adrenoceptors.

Abstract

Migraine is a disorder associated with increased plasma concentrations of calcitonin gene-related peptide (CGRP). CGRP, a neuropeptide released from activated trigeminal sensory nerves, dilates cranial blood vessels and transmits vascular nociception. Moreover, several antimigraine drugs inhibit the dural neurogenic vasodilatation to trigeminal stimulation. Hence, this study investigated in anaesthetized dogs the effects of the alpha(2)-adrenoceptor agonist, clonidine, on the external carotid vasodilator responses to capsaicin, alpha-CGRP and acetylcholine. 1-min intracarotid infusions of capsaicin (10, 18, 30 and 56 microg/min), alpha-CGRP (0.1, 0.3, 1 and 3 microg/min) and acetylcholine (0.01, 0.03, 0.1 and 0.3 microg/min) produced dose-dependent increases in external carotid conductance without affecting blood pressure or heart rate. Interestingly, the carotid vasodilator responses to capsaicin, but not those to alpha-CGRP or acetylcholine, were partially inhibited after clonidine (total dose: 24.4 microg/kg, i.v.); in contrast, equivalent volumes of saline did not affect the responses to capsaicin, alpha-CGRP or acetylcholine. The inhibitory responses to clonidine were antagonized by i.v. administration of the alpha(2)-adrenoceptor antagonists rauwolscine (alpha(2A/2B/2C); 300 microg/kg), BRL44408 (alpha(2A); 1000 microg/kg) or MK912 (alpha(2C); 100 and 300 microg/kg), but not by imiloxan (alpha(2B); 1000 microg/kg). These results suggest that clonidine inhibits the external carotid vasodilator responses to capsaicin by peripheral trigeminovascular and/or central mechanisms; this inhibitory response to clonidine seems to be predominantly mediated by alpha(2A)-adrenoceptors and, to a much lesser extent, by alpha(2C)-adrenoceptors.