The neurotrophic factor artemin and its receptor GFRα3 mediate migraine-like pain via the ion channel TRPM8.

Abstract

Migraine has a strong genetic foundation, including both monogenic and polygenic types. The former are rare, with most migraine considered polygenic, supported by genome-wide association studies (GWAS) identifying numerous genetic variants associated with migraine risk. Surprisingly, some of the most common mutations are associated with TRPM8, a non-selective cation channel that is the primary sensor of cold temperatures in primary afferent neurons of the somatosensory system. However, it is unlikely that the temperature sensitivity of TRPM8 underlies its role in migraine pathogenesis. To define the basis of the channel's involvement, we reasoned that cellular processes that increase cold sensitivity in the skin, such as the neurotrophic factor artemin, via its receptor GFRα3, also mediate TRPM8-associated migraine-like pain in the meninges. To investigate the role of artemin and GFRα3 in preclinical rodent migraine models, we infused nitroglycerin acutely and chronically, and measured changes in periorbital and hind paw mechanical sensitivity in male and female mice lacking GFRα3, after neutralization of free artemin with specific monoclonal antibodies, or by systemic treatment with a TRPM8-specific antagonist. Further, in wildtypes and mice lacking either GFRα3 or TRPM8, we tested the effects of supradural infusions of a mix of inflammatory mediators, artemin, and a TRPM8-specific agonist on migraine-related pain in mice. We find that mechanical allodynia induced by systemic nitroglycerin, or supradural infusion of inflammatory mediators, involves GFRα3. In addition, neutralization of circulating artemin reduces the nitroglycerin phenotype, demonstrating the importance of this neurotrophic pathway. Further, we show TRPM8 expression in the meninges and that direct supradural infusion of either a TRPM8-specific agonist or artemin itself produces mechanical allodynia, the latter dependent on TRPM8 and ameliorated by concurrent treatment with sumatriptan. These results indicate that neuroinflammatory events in the meninges can produce migraine-like pain in mice via artemin and GFRα3, likely acting upstream of TRPM8, providing a novel pathway that may contribute to migraine pathogenesis.