The CNS as a primary target for migraine therapeutics

Migraine is a debilitating neurological disorder characterized by recurring headache attacks lasting 4-72 hours. Although migraine is common, the pathophysiological causes of this disorder remain unknown. Evidence suggests the importance of the central nervous system (CNS) in the pathology of all migraine variants; however, drug development remains focused on peripheral targets. Migraine therapeutics including triptans, calcitonin generelated peptide (CGRP) antagonists, and monoclonal antibodies against CGRP and its receptor are not thought to cross the blood-brain barrier (BBB).Nonetheless, triptans and CGRP antagonists have been shown experimentally to bind to and exert actions in migraine-relevant regions of the CNS. Some studies have observed increased permeabilityof the BBB in migraine, which may partiallyaccount for the CNS activity of these drugs. Adding to the complexity of the disorder, differentmigraine variants such as familial hemiplegicmigraine (FHM), migraine with aura, and migrainewithout aura have different underlying pathological mechanisms. In FHM and migraine with aura, cortical spreading depression (CSD) is thought to trigger both the aura phase as well as meningeal primary nociceptor activation in migraine. Thecause of CSD in patients experiencing migraine with aura is largely unknown; however studiesindicate that sex hormones, corticosteroids, inflammatory mediators such as CGRP, and genetic factors play an important role. Furthermore, CSD has also been correlated with an increase in BBB permeability, strengthening the argument for migraine drug activity in the CNS. It is clear from the mounting evidence, both preclinical and clinical, that CNS mechanisms play an important role in the underlying pathology of migraine. It is therefore vital that future studies continue toinvestigate these CNS mechanisms in order tocreate new, more effective treatments to treat and prevent migraine.