Mechanisms Underlying Migraine Headache Pathophysiology: Novel Insights From Preclinical Models

Migraine is a highly prevalent and complex disorder characterized by severe, unilateral, pulsating headaches associated with photophobia, phonophobia, nausea, and, in some cases, auras. Headaches are the most disabling component of the condition and, while treatments have improved over the last few decades, the complexity of migraine pathophysiology has made it extremely challenging to develop highly efficacious therapeutics. Patients are particularly susceptible to attacks following exposure to normally innocuous stimuli and mounting clinical and preclinical evidence suggests that this may be due to maladaptive sensitization of the trigeminal sensory system. Although it is widely accepted that the trigeminovascular system is responsible for the pain associated with migraine, the mechanisms by which dura-projecting trigeminal ganglia (TG) nociceptors become activated and sensitized remain poorly understood. In other preclinical pain models, reactive nitroxidative species such as nitric oxide (NO), but particularly peroxynitrite (PN), have been implicated in establishing long-lasting hypersensitivity and targeting these molecules has achieved antinociceptive efficacy. Despite NO donors being one of the most consistent triggers of headache, little is known about the role of nitroxidative species in migraine mechanisms. Similarly, other mechanisms that have been shown to contribute to nociceptor activation and sensitization in preclinical pain models, such as translational dysregulation of mRNA, have not been studied in the context of migraine. Thus, the goal of our research was to utilize pharmacological techniques and transgenic animals in our novel preclinical migraine models to further understand the mechanisms that contribute to the development and persistence of migraine headache. The first part of our work highlights a novel, critical role for PN formation in mediating long-lasting hypersensitivity in preclinical models of migraine while the second part of our work defines MNK regulation of eIF4E phosphorylation as a key target for migraine therapeutics.