Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, 70211, Finland.
Department of Applied Physics, University of Eastern Finland, Kuopio, 70211, Finland.
Neuropharmacology. 2019 May 1;149:113-123. doi: 10.1016/j.neuropharm.2019.02.015. Epub 2019 Feb 13.
Recent discovery of mechanosensitive Piezo receptors in trigeminal ganglia suggested the novel molecular candidate for generation of migraine pain. However, the contribution of Piezo channels in migraine pathology was not tested yet. Therefore, in this study, we explored a potential involvement of Piezo channels in peripheral trigeminal nociception implicated in generation of migraine pain.
We used immunohistochemistry, calcium imaging, calcitonin gene related peptide (CGRP) release assay and electrophysiology in mouse and rat isolated trigeminal neurons and rat hemiskulls to study action of various stimulants of Piezo receptors on migraine-related peripheral nociception.
We found that essential (35%) fraction of isolated rat trigeminal neurons responded to chemical Piezo1 agonist Yoda1 and about a half of Yoda1 positive neurons responded to hypo-osmotic solution (HOS) and a quarter to mechanical stimulation by focused ultrasound (US). In ex vivo hemiskull preparation, Yoda1 and HOS largely activated persistent nociceptive firing in meningeal branches of trigeminal nerve. By using our novel cluster analysis of pain spikes, we demonstrated that 42% of fibers responded to Piezo1 agonist and 20% of trigeminal fibers were activated by Yoda1 and by capsaicin, suggesting expression of Piezo receptors in TRPV1 positive peptidergic nociceptive nerve fibers. Consistent with this, Yoda1 promoted the release of the key migraine mediator CGRP from hemiskull preparation.
Taken together, our data suggest the involvement of mechanosensitive Piezo receptors, in particular, Piezo1 subtype in peripheral trigeminal nociception, which provides a new view on mechanotransduction in migraine pathology and suggests novel molecular targets for anti-migraine medicine.
最近在三叉神经节中发现了机械敏感的 Piezo 受体，这为偏头痛疼痛的产生提供了新的分子候选物。然而，Piezo 通道在偏头痛发病机制中的作用尚未得到验证。因此，在这项研究中，我们探讨了 Piezo 通道在外周三叉神经伤害感受中的潜在作用，该作用涉及偏头痛疼痛的产生。
我们使用免疫组织化学、钙成像、降钙素基因相关肽（CGRP）释放测定和小鼠和大鼠分离的三叉神经神经元和大鼠半颅骨中的电生理学方法，研究了各种 Piezo 受体激动剂对偏头痛相关外周伤害感受的作用。
我们发现，分离的大鼠三叉神经神经元的必需（35%）部分对化学 Piezo1 激动剂 Yoda1 有反应，大约一半的 Yoda1 阳性神经元对低渗溶液（HOS）和聚焦超声（US）的机械刺激有反应。在离体半颅骨制备物中，Yoda1 和 HOS 主要激活三叉神经脑膜分支中的持续性伤害性放电。通过使用我们新的疼痛尖峰聚类分析，我们证明了 42%的纤维对 Piezo1 激动剂有反应，20%的三叉神经纤维对 Piezo1 激动剂和辣椒素有反应，这表明 Piezo 受体在 TRPV1 阳性肽能伤害感受神经纤维中表达。与此一致，Yoda1 促进了半颅骨制备物中关键偏头痛介质 CGRP 的释放。
总之，我们的数据表明，机械敏感的 Piezo 受体，特别是 Piezo1 亚型，参与了外周三叉神经伤害感受，这为偏头痛发病机制中的机械转导提供了新的视角，并为抗偏头痛药物提供了新的分子靶点。
