Ž . European Journal of Pharmacology 328 1997 37–40 Short communication Rizatriptan has central antinociceptive effects against durally evoked responses Michael J. Cumberbatch ) , Raymond G. Hill, Richard J. Hargreaves Merck Sharp & Dohme Research Laboratories, Neuroscience Research Center, Terlings Park, Harlow, Essex CM20 2QR, UK Received 23 January 1997; revised 2 April 1997; accepted 11 April 1997 Abstract The 5-HT receptor agonist rizatriptan constricts intracranial, extracerebral blood vessels, inhibits neurogenic vasodilation and 1Br1D extravasation in the meninges and is effective clinically against migraine. The present study has investigated whether rizatriptan may also Ž . have activity at 5-HT receptors within the central nervous system CNS that contributes to its antimigraine effects. Action 1Br1D potentials evoked by electrical stimulation of the dura-mater were recorded extracellularly from single neurones in the trigeminal nucleus caudalis in anaesthetized rats. Rizatriptan dose dependently inhibited these nociceptive dural responses by up to 63 "9% after 3 mgrkg, i.v. Rizatriptan therefore has central activity which may contribute to its efficacy against migraine headache. Keywords: 5-HT receptor agonist; Rizatriptan; Trigeminal nucleus caudalis; Migraine; Electrophysiology 1Br1D 1. Introduction Ž . The trigeminal V caudal nucleus is the primary relay site for somatosensory information from pericranial and Ž . intracranial tissues see Cooper and Sessle, 1993 . This site of nociceptive processing is believed to underlie some aspects of migraine head pain since noxious stimulation of the dura and meningeal blood vessels can evoke electro- Ž . physiological responses Strassman et al., 1986 and c-fos Ž . expression Kaube et al., 1993b; Strassman et al., 1994 in the trigeminal nucleus caudalis. Rizatriptan is a potent selective 5-HT receptor 1Br1D agonist which has been shown to be clinically useful in the Ž . treatment of migraine headache Visser et al., 1996 . Riza- triptan selectively constricts isolated human middle Ž . meningeal arteries Longmore et al., 1997 and inhibits Ž . neurogenic dural vasodilatation Hargreaves et al., 1997 Ž . and extravasation Shepheard et al., 1994 . These periph- eral actions are thought to contribute to the antimigraine activity of rizatriptan. The observation that 5-HT receptor 1 agonists have general antinociceptive properties in the Ž . spinal cord Zemlan et al., 1988 prompted experimental ) Ž . Ž . Corresponding author. Tel.: 44-1279 440-644; Fax: 44-1279 440- 390. studies to assess the involvement of central trigeminal 5-HT receptors in the modulation of nociceptive neu- 1Br1D rotransmission from cranial structures since these sites could also be involved in the antimigraine effects of brain penetrant 5-HT receptor agonists. Systemic sumatrip- 1Br1D tan has been shown electrophysiologically to attenuate Ž . dural nociceptive responses Kaube et al., 1993a and c-fos Ž . expression Shepheard et al., 1995 in the nucleus caudalis under experimental conditions where the blood–brain bar- rier is disrupted. Furthermore, anatomical studies show a high concentration of 5-HT receptors in the trigemi- 1Br1D Ž nal ganglion of animals and humans Bruinvels et al., . 1992; Rebeck et al., 1994; Bouchelet et al., 1996 and in Ž . the V caudal nucleus Mills and Martin, 1995 . Clinical studies with rizatriptan showed that it produced good dose-related pain relief in migraine patients but that at high dose levels there was a concomitant increase in the inci- Ž . dence of central adverse events Visser et al., 1996 . This response profile indicated that rizatriptan penetrated the CNS and suggests that central actions may contribute to its antimigraine efficacy. The present studies in vivo have therefore investigated whether the selective 5-HT re- 1Br1D ceptor agonist rizatriptan has a central antinociceptive site of action within the trigeminal nucleus caudalis in the presence of an intact blood–brain barrier. 0014-2999r97r$17.00 Copyright q 1997 Elsevier Science B.V. All rights reserved.