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The Journal of Neuroscience, June 22, 2005, 25(25):5877-5883; doi:10.1523/JNEUROSCI.0869-05.2005

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Neurobiology of Disease
The Nonpeptide Calcitonin Gene-Related Peptide Receptor Antagonist BIBN4096BS Lowers the Activity of Neurons with Meningeal Input in the Rat Spinal Trigeminal Nucleus

Michael Jochen Marco Fischer, Stanislav Koulchitsky, and Karl Messlinger

Institute of Physiology and Experimental Pathophysiology, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany

Calcitonin gene-related peptide (CGRP) has been suggested to play a major role in the pathogenesis of migraines and other primary headaches. CGRP may be involved in the control of neuronal activity in the spinal trigeminal nucleus (STN), which integrates nociceptive afferent inputs from trigeminal tissues, including intracranial afferents. The activity of STN neurons is thought to reflect the activity of central trigeminal nociceptive pathways causing facial pain and headaches in humans.

In a rat model of meningeal nociception, single neuronal activity in the STN was recorded. All units had receptive fields located in the exposed parietal dura mater. Heat and cold stimuli were repetitively applied to the dura in a fixed pattern of ramps and steps. The nonpeptide CGRP receptor antagonist BIBN4096BS was topically applied onto the exposed dura or infused intravenously.

BIBN4096BS (300 µg/kg, i.v.) reduced spontaneous activity by 30%, the additional dose of 900 µg/kg intravenously by 50% of the initial activity, whereas saline had no effect. The activity evoked by heat ramps was also reduced after BIBN4096BS (900 µg/kg, i.v.) by 50%. Topical administration of BIBN4096BS (1 mM) did not significantly change the spontaneous neuronal activity within 15 min.

We conclude that the endogenous release of CGRP significantly contributes to the maintenance of spontaneous activity in STN neurons. Blockade of CGRP receptors, possibly at central and peripheral sites, may therefore be an effective way to decrease nociceptive transmission. This may offer a new therapeutic strategy for the treatment of facial pain and primary headaches.

Key words: migraine; headache; meningeal nociception; olcegepant; pain; neuropeptide; CGRP

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Received March 4, 2005; revised April 21, 2005; accepted May 13, 2005.

This article has been cited by other articles:

				M.-L. Sixt, K. Messlinger, and M. J. M. Fischer Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus Brain, November 1, 2009; 132(11): 3134 - 3141. [Abstract] [Full Text] [PDF]

				J. Meng, S. V. Ovsepian, J. Wang, M. Pickering, A. Sasse, K. R. Aoki, G. W. Lawrence, and J. O. Dolly Activation of TRPV1 Mediates Calcitonin Gene-Related Peptide Release, Which Excites Trigeminal Sensory Neurons and Is Attenuated by a Retargeted Botulinum Toxin with Anti-Nociceptive Potential J. Neurosci., April 15, 2009; 29(15): 4981 - 4992. [Abstract] [Full Text] [PDF]

				R. C. Bucelli, E. A. Gonsiorek, W.-Y. Kim, D. Bruun, R. A. Rabin, D. Higgins, and P. J. Lein Statins Decrease Expression of the Proinflammatory Neuropeptides Calcitonin Gene-Related Peptide and Substance P in Sensory Neurons J. Pharmacol. Exp. Ther., March 1, 2008; 324(3): 1172 - 1180. [Abstract] [Full Text] [PDF]

				C. A. Salvatore, J. C. Hershey, H. A. Corcoran, J. F. Fay, V. K. Johnston, E. L. Moore, S. D. Mosser, C. S. Burgey, D. V. Paone, A. W. Shaw, et al. Pharmacological Characterization of MK-0974 [N-[(3R,6S)-6-(2,3-Difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a Potent and Orally Active Calcitonin Gene-Related Peptide Receptor Antagonist for the Treatment of Migraine J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 416 - 421. [Abstract] [Full Text] [PDF]

				Z. Zhang, C. S. Winborn, B. Marquez de Prado, and A. F. Russo Sensitization of Calcitonin Gene-Related Peptide Receptors by Receptor Activity-Modifying Protein-1 in the Trigeminal Ganglion J. Neurosci., March 7, 2007; 27(10): 2693 - 2703. [Abstract] [Full Text] [PDF]

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