Cabañero David, Carter Edward P, González-Cano Rafael, Cobos Enrique J, Fernández-Carvajal Asia, Ferrer-Montiel Antonio
Institute of Research, Development and Innovation in Healthcare Biotechnology of Elche (IDiBE), University Miguel Hernández of Elche, Altabix-3, 5, Elche, 03207, Spain.
Department of Life Sciences, University of Bath, Claverton Down, Bath, BA2 7AY, UK.
J Headache Pain. 2025 Jun 23;26(1):146. doi: 10.1186/s10194-025-02082-4.
Genetic variations in the Trpm8 gene that encodes the cold receptor TRPM8 have been linked to protection against polygenic migraine, a disabling condition primarily affecting women. Noteworthy, TRPM8 has been recently found in brain areas related to emotional processing, suggesting an unrecognized role in migraine comorbidities. Here, we use mouse behavioural models to investigate the role of Trpm8 in migraine-related phenotypes. Subsequently, we test the efficacy of rapamycin, a clinically relevant TRPM8 agonist, in these behavioural traits and in human induced pluripotent stem cell (iPSC)-derived sensory neurons.
We report that Trpm8 null mice exhibited impulsive and depressive-like behaviours, while also showing frequent pain-like facial expressions detected by an artificial intelligence algorithm. In a nitroglycerin-induced migraine model, Trpm8 knockout mice of both sexes developed anxiety and mechanical hypersensitivity, whereas wild-type females also displayed depressive-like phenotype and hypernociception. Notably, rapamycin alleviated pain-related behaviour through both TRPM8-dependent and independent mechanisms but lacked antidepressant activity, consistent with a peripheral action. The macrolide ionotropically activated TRPM8 signalling in human sensory neurons, emerging as a new candidate for intervention.
Together, our findings underscore the potential of TRPM8 for migraine relief and its involvement in affective comorbidities, emphasizing the importance of addressing emotional symptoms to improve clinical outcomes for migraine sufferers, especially in females.
编码冷感受器TRPM8的Trpm8基因的遗传变异与预防多基因偏头痛有关，多基因偏头痛是一种主要影响女性的致残性疾病。值得注意的是，最近在与情绪处理相关的脑区发现了TRPM8，这表明它在偏头痛合并症中具有未被认识的作用。在这里，我们使用小鼠行为模型来研究Trpm8在偏头痛相关表型中的作用。随后，我们测试了雷帕霉素（一种临床上相关的TRPM8激动剂）在这些行为特征以及人诱导多能干细胞（iPSC）衍生的感觉神经元中的功效。
我们报告说，Trpm8基因敲除小鼠表现出冲动和抑郁样行为，同时还表现出通过人工智能算法检测到的频繁的疼痛样面部表情。在硝酸甘油诱导的偏头痛模型中，两性的Trpm8基因敲除小鼠都出现了焦虑和机械性超敏反应，而野生型雌性小鼠也表现出抑郁样表型和痛觉过敏。值得注意的是，雷帕霉素通过TRPM8依赖性和非依赖性机制减轻了疼痛相关行为，但缺乏抗抑郁活性，这与外周作用一致。大环内酯类药物在人感觉神经元中以离子otropic方式激活TRPM8信号，成为一种新的干预候选药物。
总之，我们的研究结果强调了TRPM8在缓解偏头痛方面的潜力及其在情感合并症中的作用，强调了解决情绪症状以改善偏头痛患者临床结果的重要性，尤其是在女性患者中。
