Content area
Full text
Migraines are a type of headache that occur with other neurological symptoms, but the pathophysiology remains unclear. In this issue of the JCI, Nelson-Maney and authors used constitutive and inducible knockouts of the CGRP receptor components, elegantly demonstrating an essential function of CGRP in modulating meningeal lymphatic vessels (MLVs) in migraine. CGRP was shown to induce rearrangement of membrane-bound gap junction proteins in MLVs, resulting in a reduced CSF flux into cervical lymph nodes. The authors also provided evidence of a primary role for CGRP in modulating neuro-immune function. Finally, by showing that blocking CGRP signaling in MLVs attenuated pain behavior associated with acute migraine in rodents, the authors provided a target for pharmacological blockade of CGRP in relation to primary headache disorders.
Migraine and the rational for targeting CGRP
Migraine is a disorder characterized by recurring headache attacks accompanied by other neurological symptoms and affects 15% of the world's population. The frequency and severity of these attacks have substantial impacts on socioprofessional and interpersonal function, and migraine ranks second or third worldwide as a cause of disability. Despite the availability of a variety of therapies targeting numerous neurotransmitter and other biological systems, many patients remain refractory to these treatments. The development of new and efficient methods to manage migraine is therefore needed and will have substantial impact on global health. In this issue of the JCI, a thoughtful study conducted by Nelson-Maney et al. (1) calls attention to lymphatic vasculature of the meninges as a potential therapeutic antimigraine target, via calcitonin generelated peptide (CGRP) signaling, which mediated multiple effects on pain, neuroinflammation, and cerebrospinal fluid (CSF) efflux in a model of migraine attack.
In clinical practice, triptans, which are synthetic serotonin receptor agonists, are first-line agents for the acute treatment of migraine, although these drugs may not be effective or may be contraindicated for certain patients. Likewise, preventive migraine agents, such as beta blockers, tricyclic antidepressants, antiepileptics, or botulinum toxin, may be ineffective or contraindicated. Several medications targeting the CGRP signaling axis have been developed and recently approved by the U.S. FDA.
The rationale for targeting CGRP for migraine stems from decades of evidence demonstrating a role for the proinflammatory, vasodilatory peptide in this disorder. CGRP is elevated during acute migraine attacks (2,...