Knight Y E, Edvinsson L, Goadsby P J
Institute of Neurology, The National Hospital for Neurology and Neurosurgery, Queen Square, London, WCIN 3BG, UK.
Neuropeptides. 1999 Feb;33(1):41-6. doi: 10.1054/npep.1999.0009.
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.
偏头痛疼痛的病理生理基础一直备受关注，其必定涉及颅血管三叉神经支配（即三叉神经血管系统）各组成部分的激活。近来，将三叉神经诱发的神经源性血浆蛋白外渗（PPE）视作疼痛模型，促使人们去寻找具有特定抗外渗特性的化合物。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发作期会释放出来。CGRP可能通过其强大的颅血管舒张作用或作用于三叉神经活动而在偏头痛中发挥作用，这两者均是5HT（1B/1D）激动剂药物的作用靶点，但CGRP本身并不会引起PPE。有人提出5HT（1B/1D）激动剂可能通过抑制硬脑膜中的PPE而产生抗偏头痛作用。阿伐曲坦和CP122,288对5HT（1B/1D）受体均具有很强的结合亲和力，但只有CP122,288是PPE的有效抑制剂。在本研究中，我们试图比较CP122,288和阿伐曲坦对猫上矢状窦（SSS）刺激后颈静脉CGRP释放的影响。在11只麻醉猫中，通过放射免疫分析法对颈外静脉血样中的CGRP水平进行了三种情况下的分析：a）对照；b）SSS刺激后1分钟；c）在药物存在的情况下SSS刺激后1分钟。刺激SSS导致颈外静脉释放CGRP（77±1 pmol/L）。在大鼠中，给予PPE抑制剂量（静脉注射100 ng/kg）时，CP122,288对CGRP释放无影响（77±6 pmol/L），而给予临床相关剂量（静脉注射50 μg/kg）时，阿伐曲坦可阻断CGRP释放。本研究表明，PPE的有效抑制剂CP122,288在临床试验中已被证明对治疗急性偏头痛发作无效，对CGRP释放无影响，而有效的抗偏头痛药物且相对较弱的PPE抑制剂阿伐曲坦则可阻断CGRP释放。这些数据强调了CGRP释放在偏头痛中的重要性及其可能独立于PPE，更重要的是表明在动物研究中其他非5HT类药理靶点可能是PPE阻断的原因。
