PDF(Pubmed)
Abstract：
BACKGROUND: Pain, an evolutionarily conserved warning system, lets us recognize threats and motivates us to adapt to those threats. Headache pain from migraine affects approximately 15% of the global population. However, the identity of any putative threat that migraine or headache warns us to avoid is unknown because migraine pathogenesis is poorly understood. Here, we show that a stress-induced increase in pituitary adenylate cyclase-activating polypeptide-38 (PACAP38), known as an initiator of allosteric load inducing unbalanced homeostasis, causes headache-like behaviour in male mice via mas-related G protein-coupled receptor B2 (MrgprB2) in mast cells.
METHODS: The repetitive stress model and dural injection of PACAP38 were performed to induce headache behaviours. We assessed headache behaviours using the facial von Frey test and the grimace scale in wild-type and MrgprB2-deficient mice. We further examined the activities of trigeminal ganglion neurons using in vivo Pirt-GCaMP Ca2+ imaging of intact trigeminal ganglion (TG).
RESULTS: Repetitive stress and dural injection of PACAP38 induced MrgprB2-dependent headache behaviours. Blood levels of PACAP38 were increased after repetitive stress. PACAP38/MrgprB2-induced mast cell degranulation sensitizes the trigeminovascular system in dura mater. Moreover, using in vivo intact TG Pirt-GCaMP Ca2+ imaging, we show that stress or/and elevation of PACAP38 sensitized the TG neurons via MrgprB2. MrgprB2-deficient mice showed no sensitization of TG neurons or mast cell activation. We found that repetitive stress and dural injection of PACAP38 induced headache behaviour through TNF-a and TRPV1 pathways.
CONCLUSIONS: Our findings highlight the PACAP38-MrgprB2 pathway as a new target for the treatment of stress-related migraine headache. Furthermore, our results pertaining to stress interoception via the MrgprB2/PACAP38 axis suggests that migraine headache warns us of stress-induced homeostatic imbalance.
METHODS: The repetitive stress model and dural injection of PACAP38 were performed to induce headache behaviours. We assessed headache behaviours using the facial von Frey test and the grimace scale in wild-type and MrgprB2-deficient mice. We further examined the activities of trigeminal ganglion neurons using in vivo Pirt-GCaMP Ca2+ imaging of intact trigeminal ganglion (TG).
RESULTS: Repetitive stress and dural injection of PACAP38 induced MrgprB2-dependent headache behaviours. Blood levels of PACAP38 were increased after repetitive stress. PACAP38/MrgprB2-induced mast cell degranulation sensitizes the trigeminovascular system in dura mater. Moreover, using in vivo intact TG Pirt-GCaMP Ca2+ imaging, we show that stress or/and elevation of PACAP38 sensitized the TG neurons via MrgprB2. MrgprB2-deficient mice showed no sensitization of TG neurons or mast cell activation. We found that repetitive stress and dural injection of PACAP38 induced headache behaviour through TNF-a and TRPV1 pathways.
CONCLUSIONS: Our findings highlight the PACAP38-MrgprB2 pathway as a new target for the treatment of stress-related migraine headache. Furthermore, our results pertaining to stress interoception via the MrgprB2/PACAP38 axis suggests that migraine headache warns us of stress-induced homeostatic imbalance.
摘要：
背景：疼痛，进化保守的预警系统，让我们认识到威胁，并激励我们适应这些威胁。偏头痛引起的头痛影响约15%的全球人口。然而,偏头痛或头痛警告我们避免的任何假定威胁的身份尚不清楚，因为对偏头痛的发病机制了解甚少。这里,我们显示了应激诱导的垂体腺苷酸环化酶激活多肽-38（PACAP38）的增加，被称为引起不平衡体内平衡的变构负荷的发起者，通过肥大细胞中与mas相关的G蛋白偶联受体B2（MrgprB2）引起雄性小鼠的头痛样行为。
方法：采用重复应激模型和硬脑膜注射PACAP38诱导头痛行为。我们使用面部vonFrey测试和grimace量表评估了野生型和MrgprB2缺陷小鼠的头痛行为。我们使用完整的三叉神经节（TG）的体内Pirt-GCaMPCa2成像进一步检查了三叉神经节神经元的活性。
结果：重复应激和硬脑膜注射PACAP38诱导MrgprB2依赖性头痛行为。重复应激后，PACAP38的血液水平升高。PACAP38/MrgprB2诱导的肥大细胞脱颗粒使硬脑膜中的三叉神经血管系统敏感。此外，使用体内完整的TGPirt-GCaMPCa2+成像，我们显示PACAP38的应激或/和升高通过MrgprB2使TG神经元敏感。MrgprB2缺陷小鼠未显示TG神经元或肥大细胞活化的致敏。我们发现重复应激和硬脑膜注射PACAP38通过TNF-a和TRPV1途径引起头痛行为。
结论：我们的发现强调了PACAP38-MrgprB2通路作为治疗应激相关性偏头痛的新靶点。此外，我们通过MrgprB2/PACAP38轴进行应激交互感受的结果提示偏头痛警告我们应激诱导的体内平衡失衡.
方法：采用重复应激模型和硬脑膜注射PACAP38诱导头痛行为。我们使用面部vonFrey测试和grimace量表评估了野生型和MrgprB2缺陷小鼠的头痛行为。我们使用完整的三叉神经节（TG）的体内Pirt-GCaMPCa2成像进一步检查了三叉神经节神经元的活性。
结果：重复应激和硬脑膜注射PACAP38诱导MrgprB2依赖性头痛行为。重复应激后，PACAP38的血液水平升高。PACAP38/MrgprB2诱导的肥大细胞脱颗粒使硬脑膜中的三叉神经血管系统敏感。此外，使用体内完整的TGPirt-GCaMPCa2+成像，我们显示PACAP38的应激或/和升高通过MrgprB2使TG神经元敏感。MrgprB2缺陷小鼠未显示TG神经元或肥大细胞活化的致敏。我们发现重复应激和硬脑膜注射PACAP38通过TNF-a和TRPV1途径引起头痛行为。
结论：我们的发现强调了PACAP38-MrgprB2通路作为治疗应激相关性偏头痛的新靶点。此外，我们通过MrgprB2/PACAP38轴进行应激交互感受的结果提示偏头痛警告我们应激诱导的体内平衡失衡.
