Ž . European Journal of Pharmacology 424 2001 53–58 www.elsevier.nlrlocaterejphar The effect of adrenergic compounds on neurogenic dural vasodilatation q Simon Akerman a , David J. Williamson b , Raymond G. Hill b , Peter J. Goadsby a, ) a Headache Group, Institute of Neurology, Queen Square, London WC1N 3BG, UK b Merck Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Harlow, UK Received 15 February 2001; received in revised form 29 May 2001; accepted 1 June 2001 Abstract The pharmacology of neurogenic trigeminovascular vasodilator responses in the dura mater is of interest for understanding the pathophysiology of migraine and to develop new therapies for this disabling common condition. Aminergic mechanisms have been implicated in migraine through direct study of amines in patients, and by inference from the pharmacology of many effective anti-migraine compounds, particularly preventative agents. This study used intravital microscopy to assess the role of aminergic Ž . transmission in neurogenic dural vasodilatation NDV by measuring directly the diameter of dural arteries in sodium pentobarbitone anaesthetised rats. Electrical stimulation of a closed cranial window produces, by local depolarisation of nerves, dural vessel dilation that is monitored continuously on-line using video-microscopy and a video dimension analyser. This dural vasodilatation was not affected by Ž . Ž . pre-treatment with an a -adrenoceptor agonist phenylephrine, 1 and 5 mgrkg , or antagonist corynanthine, 1 and 2 mgrkg , nor by an 1 Ž . Ž . a -adrenoceptor agonist UK14,304, 5 mgrkg or antagonist yohimbine, 1 and 3 mgrkg . Similarly, we saw no effect of b-adrenoceptor 2 Ž . blockade propranolol, 1 and 3 mgrkg . The lack of an inhibitory effect of UK14,304 the model of neurogenic dural Õasodilation contrasts with its effect in neurogenic dural plasma protein extraÕasation model. The lack of inhibition of b-adrenoceptor antagonists in the neurogenic vasodilatation model contrasts with their usefulness as migraine prophylactics, and suggests that their mechanism of action in migraine is unlikely to be through sensory trigeminal fibre terminals at the neurovascular junction. Moreover, the data indicate that the adrenergic system does not play a significant role in neurogenic dural vasodilation. q 2001 Elsevier Science B.V. All rights reserved. Keywords: Trigeminovascular; Migraine; Headache; Adrenergic compound 1. Introduction Ž . Migraine is a common Stewart et al., 1992 and dis- Ž . abling Menken et al., 2000 condition whose pathogenesis is not yet completely understood. The often reported throb- Ž bing quality of the pain Headache Classification Commit- . tee of The International Headache Society, 1988 has suggested a pivotal role for the cranial blood vessels and Ž . their trigeminal innervation Wolff, 1963 . One approach to studying the pharmacology of the trigeminal innervation of the dural vessels has been to directly observe changes in meningeal vessel diameter while activating the neurovas- Ž cular bundle with electrical stimulation Williamson et al., . 1997b . This approach offers the opportunity to study q Presented in preliminary form at Headache World 2000, London, Ž . UK, 3–7 September, 2000 Akerman et al., 2000 . ) Corresponding author. Tel.: q 44-20-7829-8749; fax: q 44-20-7813- 0349. Ž . E-mail address: peterg@ion.ucl.ac.uk P.J. Goadsby . receptor systems that are implicated in migraine, such as those implicated through therapeutic responses, in a con- trolled, stable model system in vivo. The trigeminal sensory fibres that innervate the dural vessels contain the potent vasodilator peptides calcitonin Ž . Ž gene-related peptide CGRP and substance P Uddman, . 1989 . CGRP and substance P both cause dilation of dural Ž vessels when given intravenously in the rat Williamson et . al., 1997a , and are released upon trigeminal ganglion Ž . stimulation in the human and cat Goadsby et al., 1988 . Stimulation of the trigeminal ganglion at sufficient intensi- ties will cause plasma protein extravasation in the dura Ž . mater Markowitz et al., 1987 , with associated local neu- Ž . ropeptide release Buzzi et al., 1991 . Neurogenic stimula- tion of the cranial window causes vasodilatation of dural vessels, such as the middle meningeal artery, and this is mediated by CGRP release from trigeminal sensory fibres Ž . Williamson et al., 1997b . Adrenergic receptor systems have been implicated in migraine by virtue of studies of catecholamines in mi- graineurs and by the pharmacology of a number of anti- 0014-2999r01r$ - see front matter q 2001 Elsevier Science B.V. All rights reserved. Ž . PII: S0014-2999 01 01111-6