Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288
Blockade of calcitonin gene-related peptide release after superior sagittal sinus stimulation in cat: a comparison of avitriptan and CP122,288
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DOI：
10.1054/npep.1999.0009
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发表时间：
1999-02
期刊：
影响因子：
2.9
通讯作者：
Y. Knight;L. Edvinsson;P. Goadsby
中科院分区：
文献类型：
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作者：
Y. Knight;L. Edvinsson;P. Goadsby
偏头痛疼痛的病理生理学基础一直受到大量关注，并且必须包括颅血管三叉神经支配（三叉神经血管系统）元素的激活。最近，考虑三叉神经诱发的神经源性血浆蛋白外渗（PPE）作为疼痛的模型，推动了对具有特定抗外渗性质的化合物的研究。降钙素基因相关肽（CGRP）是三叉神经血管激活的标志物，在偏头痛和丛集性头痛的头痛期释放。CGRP可能通过其有效的脑血管扩张作用或通过对三叉神经活动的作用在偏头痛中起作用，这两者都是5 HT（1B/1D）激动剂药物的靶点，但本身不产生PPE。已经表明，5 HT（1B/1D）激动剂可能通过抑制硬脑膜中的PPE而具有抗偏头痛作用。阿维曲坦和CP 122，288都对5 HT（1B/1D）受体具有强结合亲和力，但只有CP 122，288是PPE的有效抑制剂。在这项研究中，我们试图比较CP 122，288和阿维曲普坦对颈静脉CGRP释放后刺激的上级矢状窦（SSS）的猫。在11只麻醉猫颈外静脉血液样本进行了分析，通过放射免疫测定法CGRP水平在三种设置：a）控制，B）1分钟后SSS刺激和c）1分钟后SSS刺激药物的存在。刺激SSS导致CGRP从颈外静脉释放（77+/-1 pmol/L）。在大鼠PPE抑制剂量（静脉注射100 ng/kg）下，CP 122，288对CGRP释放无影响（77+/-6 pmol/L），而在临床相关剂量（静脉注射50 μ g/kg）下，阿曲普坦阻断CGRP释放。这项研究表明，PPE的有效抑制剂CP 122，288，在临床试验中已被证明是无效的治疗急性偏头痛发作，对CGRP的释放没有影响，而有效的抗偏头痛药物和相对无效的PPE抑制剂，avitriptan，阻断CGRP的释放。这些数据强调了CGRP释放的重要性及其在偏头痛中可能独立于PPE，更重要的是表明其他非基于5 HT的药理学靶点可能解释了动物研究中PPE的阻滞作用。
The pathophysiological basis for the pain of migraine has been the subject of substantial attention and must include activation of elements of the trigeminal innervation of the cranial vessels, the trigeminovascular system. Recently, consideration of trigeminal-evoked neurogenic plasma protein extravasation (PPE) as a model for the pain has driven the search for compounds with specific anti-extravasation properties. Calcitonin gene-related peptide (CGRP) is a marker for trigeminovascular activation and is released during the headache phase of migraine and cluster headache. CGRP may have a role in migraine through its potent cranial vasodilator effects or by an action on trigeminal nerve activity, both of which are targeted by 5HT(1B/1D)agonist drugs but does not itself produce PPE. It has been suggested that 5HT(1B/1D)agonists may have an anti-migraine effect via inhibition of PPE in the dura mater. Avitriptan and CP122,288 both have strong binding affinities for 5HT(1B/1D)receptors, but only CP122,288 is a potent inhibitor of PPE. In this study we sought to compare the effects of CP122,288 and avitriptan on jugular vein CGRP release after stimulation of the superior sagittal sinus (SSS) in the cat. In eleven anaesthetized cats external jugular vein blood samples were analyzed by radioimmunoassay for CGRP levels in three settings: a) control, b) 1 min after SSS stimulation and c) 1 min after SSS stimulation in presence of drug. Stimulation of the SSS resulted in release of CGRP from the external jugular vein (77+/-1 pmol/L). At a PPE-inhibitory dose in rat (100 ng/kg intravenously) CP122, 288 had no effect on CGRP release (77+/-6 pmol/L) whereas at a clinically relevant dose (50 microgram/kg intravenously) avitriptan blocked CGRP release. This study demonstrates that the potent inhibitor of PPE, CP122, 288, which has been shown in clinical trials to be ineffective in treating acute migraine attacks, had no effect on CGRP release, whereas the effective anti-migraine drug and relatively impotent inhibitor of PPE, avitriptan, blocked CGRP release. These data emphasize the importance of CGRP release and its possible independence from PPE in migraine and more importantly suggest that other non-5HT-based pharmacological targets may account for PPE blockade in animal studies.