Department of Neuroscience, University of Texas at Dallas, 800 West Campbell Rd, Richardson, TX, 75080, USA.
Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, 75080, USA.
J Headache Pain. 2023 Apr 19;24(1):42. doi: 10.1186/s10194-023-01574-5.
Migraine is a severely debilitating disorder that affects millions of people worldwide. Studies have indicated that activation of protease-activated receptor-2 (PAR2) in the dura mater causes headache responses in preclinical models. It is also well known that vasodilators such as nitric oxide (NO) donors can trigger migraine attacks in migraine patients but not controls. In the current study we examined whether activation of PAR2 in the dura causes priming to the NO donor glyceryl trinitrate (GTN).
A preclinical behavioral model of migraine was used where stimuli (PAR2 agonists: 2at-LIGRL-NH (2AT) or neutrophil elastase (NE); and IL-6) were applied to the mouse dura through an injection made at the intersection of the lamdoidal and sagittal sutures on the skull. Following dural injection, periorbital von Frey thresholds and facial grimace responses were measured until their return to baseline. GTN was then given by intraperitoneal injection and periorbital hypersensitivity and facial grimace responses observed until they returned to baseline.
We found that application of the selective PAR2 agonist 2at-LIGRL-NH (2AT) onto the dura causes headache-related behavioral responses in WT but not PAR2 mice with no differences between sexes. Additionally, dural PAR2 activation with 2AT caused priming to GTN (1 mg/kg) at 14 days after primary dural stimulation. PAR2 mice showed no priming to GTN. We also tested behavioral responses to the endogenous protease neutrophil elastase, which can cleave and activate PAR2. Dural neutrophil elastase caused both acute responses and priming to GTN in WT but not PAR2 mice. Finally, we show that dural IL-6 causes acute responses and priming to GTN that is identical in WT and PAR2 mice, indicating that IL-6 does not act through PAR2 in this model.
These results indicate that PAR2 activation in the meninges can cause acute headache behavioral responses and priming to an NO donor, and support further exploration of PAR2 as a novel therapeutic target for migraine.
偏头痛是一种严重影响全球数百万人的致残性疾病。研究表明，在临床前模型中，硬脑膜中蛋白酶激活受体-2（PAR2）的激活会引起头痛反应。众所周知，血管扩张剂，如一氧化氮（NO）供体，可以引发偏头痛患者的偏头痛发作，但不会引发对照者。在目前的研究中，我们研究了硬脑膜中 PAR2 的激活是否会引发对 NO 供体硝化甘油（GTN）的预激。
使用偏头痛的临床前行为模型，其中通过在颅骨的矢状缝和人字缝相交处的注射将刺激物（PAR2 激动剂：2at-LIGRL-NH（2AT）或中性粒细胞弹性蛋白酶（NE）；和 IL-6）应用于小鼠硬脑膜。硬脑膜注射后，测量眶周 von Frey 阈值和面部痛苦表情反应，直到其恢复基线。然后通过腹腔内注射给予 GTN，并观察眶周过敏和面部痛苦表情反应，直到它们恢复基线。
我们发现，选择性 PAR2 激动剂 2at-LIGRL-NH（2AT）在硬脑膜上的应用会导致 WT 小鼠但不是 PAR2 小鼠产生与头痛相关的行为反应，且男女之间没有差异。此外，2AT 激活硬脑膜 PAR2 会导致 GTN（1mg/kg）在初次硬脑膜刺激后 14 天出现预激。PAR2 小鼠对 GTN 没有预激。我们还测试了对内源性蛋白酶中性粒细胞弹性蛋白酶的行为反应，中性粒细胞弹性蛋白酶可以切割和激活 PAR2。硬脑膜中性粒细胞弹性蛋白酶在 WT 小鼠中引起急性反应和 GTN 的预激，但在 PAR2 小鼠中没有。最后，我们发现硬脑膜中的 IL-6 会引起急性反应和 GTN 的预激，WT 和 PAR2 小鼠之间的反应相同，表明在该模型中 IL-6 不通过 PAR2 起作用。
这些结果表明，脑膜中 PAR2 的激活会引起急性头痛行为反应和对 NO 供体的预激，并支持进一步探索 PAR2 作为偏头痛的一种新的治疗靶点。
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