Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA.
Molecular and Computational Biology Graduate Program, University of Southern California, Los Angeles, CA, USA.
Cephalalgia. 2024 Nov;44(11):3331024241297679. doi: 10.1177/03331024241297679.
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 linked with migraine risk. Surprisingly, some of the most common mutations are associated with transient receptor potential melastatin 8 (TRPM8), a non-selective cation channel that is the primary sensor of cold temperatures in cutaneous primary afferents of the somatosensory system. However, it is unlikely that the temperature sensitivity of TRPM8 is relevant in migraine-related tissues, such as the meninges, suggesting other activation mechanisms underly its role in migraine pathogenesis. Thus, 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 glial cell-line derived neurotrophic factor family receptor alpha-3 (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 mice lacking GFRα3 we tested the effects of supradural infusions of a mix of inflammatory mediators, as well as tested if dura stimulation with artemin or a TRPM8-specific agonist induce 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 in headaches. 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, with 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 headaches or migraine pathogenesis.
偏头痛具有很强的遗传基础，包括单基因和多基因类型。前者很少见，大多数偏头痛被认为是多基因的，全基因组关联研究（GWAS）确定了许多与偏头痛风险相关的遗传变异。令人惊讶的是，一些最常见的突变与瞬时受体电位 melastatin 8（TRPM8）有关，TRPM8 是感觉系统皮肤初级传入中的非选择性阳离子通道，是冷温度的主要传感器。然而，TRPM8 的温度敏感性不太可能与偏头痛相关组织（如脑膜）相关，这表明其在偏头痛发病机制中的作用存在其他激活机制。因此，为了确定通道参与的基础，我们推断，增加皮肤冷敏感性的细胞过程，例如神经营养因子 artemin，通过其受体胶质细胞衍生的神经营养因子家族受体 alpha-3（GFRα3），也介导脑膜中与 TRPM8 相关的偏头痛样疼痛。
为了研究 artemin 和 GFRα3 在临床前啮齿动物偏头痛模型中的作用，我们在雄性和雌性缺乏 GFRα3 的小鼠中急性和慢性输注硝化甘油，并测量眶周和后爪机械敏感性的变化，然后用特异性单克隆抗体中和游离的 artemin，或用 TRPM8 特异性拮抗剂进行全身治疗。此外，在缺乏 GFRα3 的小鼠中，我们测试了硬膜上输注混合炎症介质的效果，以及测试脑膜刺激用 artemin 或 TRPM8 特异性激动剂是否会引起小鼠偏头痛相关疼痛。
我们发现，全身硝化甘油或硬膜上输注炎症介质引起的机械性痛觉过敏涉及 GFRα3。此外，中和循环中的 artemin 可减轻硝化甘油表型，表明这种神经营养途径在头痛中的重要性。此外，我们在脑膜中发现了 TRPM8 的表达，并且直接硬膜上输注 TRPM8 特异性激动剂或 artemin 本身会引起机械性痛觉过敏，后者依赖于 TRPM8，并用舒马曲坦同时治疗可改善。
这些结果表明，脑膜中的神经炎症事件可以通过 artemin 和 GFRα3 在小鼠中产生偏头痛样疼痛，可能作用于 TRPM8 的上游，提供一种可能导致头痛或偏头痛发病机制的新途径。
