Basic Science: Prejunctional and Presynaptic Trigeminovascular Targets: What Preclinical Evidence Is There?

Inhibition of trigeminovascular nociceptive traffic by a prejunctional/presynaptic mechanism is an attractive approach for the treatment of migraine. It has been shown that blocking the presumed postsynaptic actions of calcitonin gene-related peptide (CGRP) is an effective acute antimigraine strategy, so that blockade of CGRP release by presynaptic inhibition also seems promising. A number of targets are reviewed including serotonin 5-HT_1F and 5-HT_1D receptor agonists, adenosine A₁ receptor agonists, nociceptin, and vanilloid VR1 receptors. For each, the preclinical rationale for their involvement in prejunctional/presynaptic mechanisms is reviewed. Development of one or more such compounds offers the exciting prospect of new nonvasoconstrictor treatments for migraine and cluster headache.