Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: Relevance to migraine pathophysiology.
Functional interactions between transient receptor potential M8 and transient receptor potential V1 in the trigeminal system: Relevance to migraine pathophysiology.
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DOI：
10.1177/0333102417712719
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发表时间：
2018-04
期刊：
影响因子：
--
通讯作者：
Suzuki N
中科院分区：
文献类型：
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作者：
Kayama Y;Shibata M;Takizawa T;Ibata K;Shimizu T;Ebine T;Toriumi H;Yuzaki M;Suzuki N
最近的全基因组关联研究已确定瞬时受体电位 M8 (TRPM8) 是偏头痛易感基因。 TRPM8 是一种非选择性阳离子通道，可介导冷感。然而，它在偏头痛病理生理学中的确切作用尚不清楚。瞬时受体电位 V1 (TRPV1) 是一种由有害热激活的非选择性阳离子通道。 TRPM8 和 TRPV1 均在三叉神经节 (TG) 神经元中表达。我们通过测量面部 TRPM8 激活对热异常性疼痛的影响并评估 TG 神经元中受体共表达的变化，研究了 TRPM8 和 TRPV1 在基于脑膜炎症的偏头痛模型中的功能作用。我们进行了逆行示踪标记来识别支配面部和硬脑膜的 TG 神经元。我们发现药理TRPM8激活逆转了脑膜炎症引起的面部热痛阈值降低，这种效应通过TRPM8基因消融而消除。在假手术动物中没有观察到热痛阈值的显着变化。脑膜炎症引起 TG 神经元中 TRPM8/TRPV1 共表达模式的动态变化，当 TRPM8 激活对热异常性疼痛的改善作用最大时，共定位最为明显。我们的示踪剂检测揭示了硬脑膜支配的 TG 神经元的存在，这些神经元将络脉发送到面部。其中大约一半为 TRPV1 阳性。我们还在使用 c-Jun N 末端激酶磷酸化作为替代标记的细胞测定中证明了 TRPM8 对 TRPV1 的功能性抑制。我们的研究结果提供了一个合理的机制来解释面部 TRPM8 激活如何通过抑制 TRPV1 活性来缓解偏头痛。面部 TRPM8 似乎是偏头痛的一个有前途的治疗靶点。
Recent genome-wide association studies have identified transient receptor potential M8 (TRPM8) as a migraine susceptibility gene. TRPM8 is a nonselective cation channel that mediates cool perception. However, its precise role in migraine pathophysiology is elusive. Transient receptor potential V1 (TRPV1) is a nonselective cation channel activated by noxious heat. Both TRPM8 and TRPV1 are expressed in trigeminal ganglion (TG) neurons. We investigated the functional roles of TRPM8 and TRPV1 in a meningeal inflammation-based migraine model by measuring the effects of facial TRPM8 activation on thermal allodynia and assessing receptor coexpression changes in TG neurons. We performed retrograde tracer labeling to identify TG neurons innervating the face and dura. We found that pharmacological TRPM8 activation reversed the meningeal inflammation-induced lowering of the facial heat pain threshold, an effect abolished by genetic ablation of TRPM8. No significant changes in the heat pain threshold were seen in sham-operated animals. Meningeal inflammation caused dynamic alterations in TRPM8/TRPV1 coexpression patterns in TG neurons, and colocalization was most pronounced when the ameliorating effect of TRPM8 activation on thermal allodynia was maximal. Our tracer assay disclosed the presence of dura-innervating TG neurons sending collaterals to the face. Approximately half of them were TRPV1-positive. We also demonstrated functional inhibition of TRPV1 by TRPM8 in a cell-based assay using c-Jun N-terminal kinase phosphorylation as a surrogate marker. Our findings provide a plausible mechanism to explain how facial TRPM8 activation can relieve migraine by suppressing TRPV1 activity. Facial TRPM8 appears to be a promising therapeutic target for migraine.
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影响因子：
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作者：
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