Lukács M, Warfvinge K, Tajti J, Fülöp F, Toldi J, Vécsei L, Edvinsson L
Department of Clinical Sciences, Division of Experimental Vascular Research, Lund University, Lund, Sweden.
Department of Neurology, University of Szeged, 6725 Semmelweis street nr. 6, Szeged, Hungary.
J Headache Pain. 2017 Dec;18(1):39. doi: 10.1186/s10194-017-0746-x. Epub 2017 Mar 23.
Migraine is a debilitating neurological disorder where trigeminovascular activation plays a key role. We have previously reported that local application of Complete Freund's Adjuvant (CFA) onto the dura mater caused activation in rat trigeminal ganglion (TG) which was abolished by a systemic administration of kynurenic acid (KYNA) derivate (SZR72). Here, we hypothesize that this activation may extend to the trigeminal complex in the brainstem and is attenuated by treatment with SZR72.
Activation in the trigeminal nucleus caudalis (TNC) and the trigeminal tract (Sp5) was achieved by application of CFA onto the dural parietal surface. SZR72 was given intraperitoneally (i.p.), one dose prior CFA deposition and repeatedly daily for 7 days. Immunohistochemical studies were performed for mapping glutamate, c-fos, PACAP, substance P, IL-6, IL-1β and TNFα in the TNC/Sp5 and other regions of the brainstem and at the C-C regions of the spinal cord.
We found that CFA increased c-fos and glutamate immunoreactivity in TNC and C-C neurons. This effect was mitigated by SZR72. PACAP positive fibers were detected in the fasciculus cuneatus and gracilis. Substance P, TNFα, IL-6 and IL-1β immunopositivity were detected in fibers of Sp5 and neither of these molecules showed any change in immunoreactivity following CFA administration.
This is the first study demonstrating that dural application of CFA increases the expression of c-fos and glutamate in TNC neurons. Treatment with the KYNA analogue prevented this expression.
偏头痛是一种使人衰弱的神经系统疾病，其中三叉神经血管激活起着关键作用。我们之前报道过，将完全弗氏佐剂（CFA）局部应用于硬脑膜会导致大鼠三叉神经节（TG）激活，而全身性给予犬尿喹啉酸（KYNA）衍生物（SZR72）可消除这种激活。在此，我们假设这种激活可能会扩展到脑干中的三叉神经复合体，并且用SZR72治疗可使其减弱。
通过将CFA应用于硬脑膜顶叶表面来实现三叉神经尾核（TNC）和三叉神经束（Sp5）的激活。在CFA沉积前腹腔内注射（i.p.）一剂SZR72，并每天重复注射7天。对TNC/Sp5、脑干的其他区域以及脊髓的C-C区域进行免疫组织化学研究，以定位谷氨酸、c-fos、垂体腺苷酸环化酶激活肽（PACAP）、P物质、白细胞介素-6（IL-6）、白细胞介素-1β（IL-1β）和肿瘤坏死因子α（TNFα）。
我们发现CFA增加了TNC和C-C神经元中c-fos和谷氨酸的免疫反应性。这种作用被SZR72减轻。在楔束和薄束中检测到PACAP阳性纤维。在Sp5的纤维中检测到P物质、TNFα、IL-6和IL-1β免疫阳性，并且在给予CFA后这些分子的免疫反应性均未显示任何变化。
这是第一项表明硬脑膜应用CFA会增加TNC神经元中c-fos和谷氨酸表达的研究。用KYNA类似物治疗可阻止这种表达。
