Recognizing the role of CGRP and CGRP receptors in migraine and its treatment.

PREMISE: The brain and the sensory nervous system contain a rich supply of calcitonin gene-related peptide (CGRP) and CGRP receptor components. Clinical studies have demonstrated a correlation between CGRP release and acute migraine headache that led to the development of CGRP-specific drugs that either abort acute attacks of migraine (gepants) or are effective as prophylaxis (antibodies). However, there is still much discussion concerning the site of action of these drugs. PROBLEM: Here we describe the most recent data related to CGRP in the trigeminal ganglion and its connections to the CNS, putative key regions involved in migraine pathophysiology. Gepants are small molecules that have limited ability to cross the blood-brain barrier (BBB), whereas CGRP antibodies are 1500 times larger molecules, and are virtually excluded from the brain, with a BBB permeability of < 0.1%. Thus we propose that the primary site of action for the antimigraine drugs is outside the CNS in areas not limited by the BBB. POTENTIAL SOLUTION: Therefore, it is reasonable to discuss the localization of CGRP and its receptor components in relation to the BBB. The trigeminovascular system, located outside the BBB, has a key role in migraine symptomatology, and it is likely targeted by the novel CGRP drugs that successfully terminate migraine headache.