The role of TRPM8 and artemin in migraine

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Migraine is one of the most debilitating disorders in humans, affecting greater than 15% of the population with minimal therapeutic avenues for migraine sufferers. The challenge in treatment is that migraine involves many sensory pathways, including irregular excitability in central and peripheral nociceptive neurons. To address this complex disorder, several groups have recently performed genome-wide associated studies (GWAS) to ascertain candidate molecules mediating migraine pathology, identifying the cold and menthol receptor TRPM8 as a migraine susceptibility gene. Interestingly, these studies identified mutations only in noncoding regions of TRPM8, therefore making it likely that these mutations alter expression levels and not channel function. While it is not known what role, if any, the channel has in migraine, TRPM8 serves an important role in pathological cold pain, suggesting there may be a corollary between cold and migraine pain. Recently, we found that the glial cell line-derived neurotrophic factor (GDNF) family ligand artemin and its receptor, GDNF family receptor alpha 3 (GFRa3), are the principle mediators of TRPM8-dependent cold pain, of note as each has also been linked to migraine. These results have led us to the hypothesis that TRPM8 channels and afferents, via altered signaling due to artemin interacting with GFRa3, are a component of the underlying mechanisms of migraine. To test this, we propose to use this exploratory mechanism to (1) determine if TRPM8 channels or neurons are involved in migraine-like pain behaviors in mice, then (2) similarly ask if artemin and GFRa3 are required for migraine pathogenesis. At the completion of this exploratory study, we will have determined if either TRPM8 or artemin/GFRa3 signaling serve a role in migraine. Moreover, the proposed experiments will determine if either of the signaling pathways under consideration are relevant for migraine, potentially serving as the foundation for future investigations.