Brain Advance Access originally published online on September 8, 2009
Brain 2009 132(11):3134-3141; doi:10.1093/brain/awp168
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Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus
1 Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Germany 2 Department of Pharmacology, University of Cambridge, UK
Correspondence to: Dr Michael Fischer, Institute of Physiology and Pathophysiology, University of Erlangen-Nürnberg, Universitätstrasse 17, 91054 Erlangen, Germany E-mail: fischer{at}physiologie1.uni-erlangen.de
Several lines of evidence suggest a major role of calcitonin gene-related peptide (CGRP) in the pathogenesis of migraine and other primary headaches. Inhibition of CGRP receptors by olcegepant and telcagepant has been successfully used to treat acute migraine and to reduce the activity of spinal trigeminal neurons involved in meningeal nociception in rodents. The site of CGRP receptor inhibition is unclear, however. In adult Wistar rats anaesthetized with isofluorane systemic intravenous infusion (0.9 mg/kg) or unilateral facial injection (1 mM in 100 µl) of capsaicin was used to induce activity in the trigeminal nociceptive system. Animals were pre-treated either by saline or olcegepant. In comparison with vehicle infusion or the non-injected side of the face, capsaicin significantly increased the expression of the activation markers Fos in the spinal trigeminal nucleus and phosphorylated extracellular signal-regulated kinase in the trigeminal ganglion. Pre-treatment with olcegepant (900 µg/kg) inhibited the capsaicin-induced expression of Fos throughout the spinal trigeminal nucleus by 57%. In contrast, the expression of phosphorylated extracellular signal-regulated kinase in the trigeminal ganglion was not changed by olcegepant pre-treatment. CGRP receptor inhibition, which has been shown to decrease spinal trigeminal activity, is likely to occur in the central nervous system rather than in the periphery including the trigeminal ganglion. This may be important for future therapeutic interventions with CGRP receptor antagonists in migraine.
Key Words: migraine; headache; BIBN4096BS; MK-0974
Abbreviations: CGRP, calcitonin gene related peptide; Fos, protein encoded by the c-Fos immediate early gene; pERK, phosphorylated extracellular signal-regulated kinase; TRPV1, transient receptor potential vanilloid 1
Received January 27, 2009. Revised May 17, 2009. Accepted May 18, 2009.