Neuroscience Graduate Program, University of Southern California, Los Angeles, CA, United States.
Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, CA, United States .
Pain. 2022 Dec 1;163(12):2380-2389. doi: 10.1097/j.pain.0000000000002635. Epub 2022 Mar 29.
Migraine is a complex neurovascular disorder that is one of the leading causes of disability and a reduced quality of life. Even with such a high societal impact, our understanding of the cellular and molecular mechanisms that contribute to migraine headaches is limited. To address this complex disorder, several groups have performed genome-wide association studies to elucidate migraine susceptibility genes, with many identifying transient receptor potential melastatin 8 (TRPM8), a cold-sensitive cation channel expressed in peripheral afferents innervating the trigeminovascular system, and the principal mediator of cold and cold pain associated with injury and disease. Interestingly, these migraine-associated single-nucleotide polymorphisms reside in noncoding regions of TRPM8, with those correlated with reduced migraine risk exhibiting lower TRPM8 expression and decreased cold sensitivity. Nonetheless, as a role for TRPM8 in migraine has yet to be defined, we sought to address this gap in our knowledge using mouse genetics and TRPM8 antagonism to determine whether TRPM8 channels or neurons are required for migraine-like pain (mechanical allodynia and facial grimace) in inducible migraine models. Our results show that both evoked and spontaneous pain behaviors are dependent on both TRPM8 channels and neurons, as well as required in both acute and chronic migraine models. Moreover, inhibition of TRPM8 channels prevented acute but not established chronic migraine-like pain. These results are consistent with its association with migraine in genetic analyses and establish that TRPM8 channels are a component of the underlying mechanisms of migraine.
偏头痛是一种复杂的神经血管性疾病，是导致残疾和生活质量下降的主要原因之一。尽管偏头痛对社会有如此大的影响，但我们对导致偏头痛的细胞和分子机制的理解仍然有限。为了治疗这种复杂的疾病，许多研究小组进行了全基因组关联研究，以阐明偏头痛易感性基因，其中许多研究确定了瞬时受体电位 melastatin 8（TRPM8），这是一种在支配三叉神经血管系统的周围传入神经中表达的冷敏感阳离子通道，是与损伤和疾病相关的冷觉和冷痛的主要介质。有趣的是，这些与偏头痛相关的单核苷酸多态性位于 TRPM8 的非编码区域，与偏头痛风险降低相关的单核苷酸多态性表现出 TRPM8 表达降低和冷敏感性降低。尽管如此，由于 TRPM8 在偏头痛中的作用尚未确定，我们试图利用小鼠遗传学和 TRPM8 拮抗剂来填补这一知识空白，以确定 TRPM8 通道或神经元是否是诱导性偏头痛模型中偏头痛样疼痛（机械性痛觉过敏和面部痛苦表情）所必需的。我们的结果表明，无论是诱发的还是自发的疼痛行为都依赖于 TRPM8 通道和神经元，并且在急性和慢性偏头痛模型中都是必需的。此外，TRPM8 通道的抑制可以预防急性但不能预防慢性偏头痛样疼痛。这些结果与遗传分析中与偏头痛的关联一致，并确立了 TRPM8 通道是偏头痛潜在机制的组成部分。
