Calcitonin gene-related peptide receptor antagonist olcegepant acts in the spinal trigeminal nucleus

• Published in: Brain (London, England : 1878) Vol. 132; no. 11; pp. 3134 - 3141
• Main Authors: Sixt, Marie-Luise, Messlinger, Karl, Fischer, Michael J. M.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01-11-2009
• Subjects: Animals; BIBN4096BS; Biological and medical sciences; Biomarkers - metabolism; Calcitonin Gene-Related Peptide - metabolism; Calcitonin Gene-Related Peptide Receptor Antagonists; Capsaicin - pharmacology; Dipeptides - metabolism; Dipeptides - pharmacology; Dipeptides - therapeutic use; Extracellular Signal-Regulated MAP Kinases - metabolism; headache; Humans; Injuries of the nervous system and the skull. Diseases due to physical agents; Male; Medical sciences; migraine; Migraine Disorders - drug therapy; Migraine Disorders - metabolism; MK-0974; Neurology; Neurons - cytology; Neurons - drug effects; Neurons - metabolism; Pain - chemically induced; Pain - metabolism; Proto-Oncogene Proteins c-fos - metabolism; Quinazolines - metabolism; Quinazolines - pharmacology; Quinazolines - therapeutic use; Rats; Rats, Wistar; Traumas. Diseases due to physical agents; Trigeminal Nucleus, Spinal - cytology; Trigeminal Nucleus, Spinal - drug effects; MK-0974; migraine; headache; BIBN4096BS; Nervous system diseases; CGRP receptor; Spinal trigeminal nucleus; Olcegepant
• ISSN: 0006-8950; 1460-2156
• DOI: 10.1093/brain/awp168

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.