Meningeal Afferent Signaling and the Pathophysiology of Migraine

Migraine is the most common neurological disorder. Attacks are complex and consist of multiple phases but are most commonly characterized by intense, unilateral, throbbing headache. The pathophysiology contributing to migraine is poorly understood and the disorder is not well managed with currently available therapeutics, often rendering patients disabled during attacks. The mechanisms most likely to contribute to the pain phase of migraine require activation of trigeminal afferent signaling from the cranial meninges and subsequent relay of nociceptive information into the central nervous system in a region of the dorsal brainstem known as the trigeminal nucleus caudalis (TNC). A three-fold higher prevalence of migraine in females implies sex-dependent mechanisms are involved in migraine. Yet, sex-dependent mechanisms of migraine remain unknown and have yet to be investigated thoroughly. Events leading to activation of meningeal afferents are unclear but nerve endings within this tissue are mechanosensitive and also express a variety of ion channels including acid-sensing (ASIC) and transient receptor-potential (TRP) channels. These properties may provide clues into the pathophysiology of migraine by suggesting that decreased extracellular pH and environmental irritant exposure in the meninges contributes to headache. Neuroplasticity is also likely to play a role in migraine given that attacks are triggered by routine events that are typically non-noxious in healthy patients and clear evidence of sensitization occurs during an attack. Where and how plasticity develops is also not clear but may include events directly on the afferents and/or within the TNC. Among the mediators potentially contributing to plasticity, calcitonin gene-related peptide (CGRP) has received the most attention within the migraine field but other mechanisms may also contribute. Ultimately, greater understanding of the molecules and mechanisms contributing to migraine will undoubtedly lead to better therapeutics and relief for the large numbers of patients across the globe who suffer from this highly disabling neurological disorder.