Cardiovascular Pharmacology Pharmacological evidence that spinal α 2C - and, to a lesser extent, α 2A -adrenoceptors inhibit capsaicin-induced vasodilatation in the canine external carotid circulation Carlos M. Villalón ⁎, Jorge Galicia-Carreón, Abimael González-Hernández, Bruno A. Marichal-Cancino, Guadalupe Manrique-Maldonado, David Centurión Departamento de Farmacobiología, Cinvestav-Coapa, Czda. de los Tenorios 235, Col. Granjas-Coapa, Deleg. Tlalpan, 14330 México D.F., Mexico abstract article info Article history: Received 28 July 2011 Received in revised form 2 March 2012 Accepted 6 March 2012 Available online xxxx Keywords: B-HT 933 BRL44408 CGRP External carotid artery JP-1302 Migraine 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 α 2 -adrenoceptors and their subtypes (i.e. α 2A , α 2B and/or α 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, α-CGRP and acetylcholine. A cannula was inserted intrathe- cally 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 α 2 -adrenoceptor agonist) and/or the α 2 -adrenoceptor antagonists rauwolscine (α 2A/2B/2C ), 2-[(4,5-dihydro-1H-imidazol-2-yl)methyl]-2,3-dihydro-1-methyl-1H-isoindole maleate (BRL44408; α 2A ), imiloxan (α 2B ) or acridin-9-yl-[4-(4-methylpiperazin-1-yl)-phenyl]amine (JP-1302; α 2C ). Infusions of capsaicin, α-CGRP and acetylcholine dose-dependently increased the exter- nal carotid conductance. Intrathecal B-HT 933 (1000 and 3100 μg) inhibited the vasodilator responses to capsaicin, but not those to α-CGRP or acetylcholine. This inhibition, abolished by rauwolscine (310 μg), was: (i) unaffected by 3100 μg imiloxan; (ii) partially blocked by 310 μg of BRL44408 or 100 μg of JP-1302; and (iii) abolished by 1000 μg of BRL44408 or 310 μg of JP-1302. Thus, intrathecal B-HT 933 inhibited the external carotid vasodilator responses to capsaicin. This response, mediated by spinal α 2 -adrenoceptors unrelated to the α 2B -adrenoceptor subtype, resembles the pharmacological pro- file of α 2C -adrenoceptors and, to a lesser extent, α 2A -adrenoceptors. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Migraine is a complex and highly prevalent neurovascular disor- der that may involve: (i) activation of the trigeminovascular complex (Holland, 2009); (ii) high circulating plasma concentrations of calci- tonin gene-related peptide (CGRP) (Goadsby et al., 2002); (iii) vaso- dilatation of intracranial arteries and of the extracranial branches of the external carotid artery, which are a source of pain in migraine (Olesen et al., 2009; Shevel, 2011a, 2011b); and (iv) a wide dysfunc- tion of the sensory system (Sprenger and Goadsby, 2009). CGRP, which is mainly located on sensory neurons and perivascular nerves (Van Rossum et al., 1997), dilates cranial blood vessels and transmits vascular nociception (Arulmani et al., 2004). The release of endogenous CGRP can be experimentally induced by either trigeminal electrical stimulation (Goadsby and Edvinsson, 1993) or chemical stimulation with capsaicin (Dux et al., 2003; Potenza et al., 1994), which activates perivascular sensory nerves through the stimulation of the transient receptor potential vanilloid type 1 (TRPV1) cation chan- nel (Caterina et al., 1997; Kim et al., 2012). In this respect, we have shown that the external carotid vasodilatation produced by intracarotid capsaicin in anaesthetized dogs is: (i) unaltered after i.v. sumatriptan (Muñoz-Islas et al., 2006), which does not easily cross an intact blood- brain barrier (Humphrey et al., 1991); (ii) inhibited after spinal (C 1 –C 3 ) administration of sumatriptan via central 5-HT 1B receptors (Muñoz-Islas et al., 2009); and (iii) inhibited after i.v. administration of the traditional lipid-soluble α 2 -adrenoceptor agonist clonidine via MK912-sensitive α 2A/2C -adrenoceptors (Jiménez-Mena et al., 2006; Table 1). These results suggest that activation of central mechanisms can inhibit capsaicin-induced cranial vasodilatation, but it is not clear the extent to which peripheral and central α 2A/2C -adrenoceptors con- tribute to the above inhibition by i.v. clonidine. Indeed, besides produc- ing peripheral inhibition on sensory perivascular CGRPergic neurons by α 2A/2C -adrenoceptors (Villalón et al., 2008), clonidine readily crosses the blood-brain barrier (McLennan, 1981; Van Zwieten et al., 1984) and, thus, it may exert central effects. Hence, an experimental European Journal of Pharmacology xxx (2012) xxx–xxx ⁎ Corresponding author. Tel.: + 52 55 5483 2854; fax: + 52 55 5483 2863. E-mail address: cvillalon@cinvestav.mx (C.M. Villalón). URL: http://farmacobiologia.cinvestav.mx/PersonalAcademico/DrCarlosMVillalonHerrera. aspx (C.M. Villalón). EJP-67894; No of Pages 7 0014-2999/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2012.03.002 Contents lists available at SciVerse ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar Please cite this article as: Villalón, C.M., et al., Pharmacological evidence that spinal α 2C - and, to a lesser extent, α 2A -adrenoceptors inhibit capsaicin-induced vasodilatation in the canine external carotid circulation, Eur. J. Pharmacol. (2012), doi:10.1016/j.ejphar.2012.03.002