PDF(Pubmed)
Abstract：
BACKGROUND: The development of several experimental migraine provocation models has significantly contributed to an understanding of the signaling mechanisms of migraine. The early history of this development and a view to the future are presented as viewed by the inventor of the models.
METHODS: Extensive knowledge of the literature was supplemented by scrutiny of reference lists.
RESULTS: Early studies used methodologies that were not blinded. They suggested that histamine and nitroglycerin (Glyceryl trinitrate, GTN) could induce headache and perhaps migraine. The development of a double blind, placebo-controlled model, and the use of explicit diagnostic criteria for induced migraine was a major step forward. GTN, donor of nitric oxide (NO), induced headache in people with- and without migraine as well as delayed migraine attacks in those with migraine. Calcitonin gene-related peptide (CGRP) did the same, supporting the development of CGRP antagonists now widely used in patients. Likewise, pituitary adenylate cyclase activating peptide (PACAP) provoked headache and migraine. Recently a PACAP antibody has shown anti migraine activity in a phase 2 trial. Increase of second messengers activated by NO, CGRP and PACAP effectively induced migraine. The experimental models have also been used in other types of headaches and have been combined with imaging and biochemical studies. They have also been used for drug testing and in genetic studies.
CONCLUSIONS: Conclusion. Human migraine provocation models have informed about signaling mechanisms of migraine leading to new drugs and drug targets. Future use of these models in imaging-, biochemistry- and genetic studies as well as in the further study of animal models is promising.
METHODS: Extensive knowledge of the literature was supplemented by scrutiny of reference lists.
RESULTS: Early studies used methodologies that were not blinded. They suggested that histamine and nitroglycerin (Glyceryl trinitrate, GTN) could induce headache and perhaps migraine. The development of a double blind, placebo-controlled model, and the use of explicit diagnostic criteria for induced migraine was a major step forward. GTN, donor of nitric oxide (NO), induced headache in people with- and without migraine as well as delayed migraine attacks in those with migraine. Calcitonin gene-related peptide (CGRP) did the same, supporting the development of CGRP antagonists now widely used in patients. Likewise, pituitary adenylate cyclase activating peptide (PACAP) provoked headache and migraine. Recently a PACAP antibody has shown anti migraine activity in a phase 2 trial. Increase of second messengers activated by NO, CGRP and PACAP effectively induced migraine. The experimental models have also been used in other types of headaches and have been combined with imaging and biochemical studies. They have also been used for drug testing and in genetic studies.
CONCLUSIONS: Conclusion. Human migraine provocation models have informed about signaling mechanisms of migraine leading to new drugs and drug targets. Future use of these models in imaging-, biochemistry- and genetic studies as well as in the further study of animal models is promising.
摘要：
背景：几种实验性偏头痛激发模型的开发极大地促进了对偏头痛信号传导机制的理解。模型的发明者介绍了这种发展的早期历史和对未来的看法。
方法：对参考文献列表的审查补充了对文献的广泛了解。
结果：早期研究使用的方法不是盲法。他们建议组胺和硝酸甘油（三硝酸甘油酯，GTN）可能会引起头痛和偏头痛。双盲的发展，安慰剂对照模型，对诱发性偏头痛使用明确的诊断标准是向前迈出的重要一步.GTN,一氧化氮（NO）的供体，在有和没有偏头痛的人中诱发头痛，以及偏头痛患者的偏头痛发作延迟。降钙素基因相关肽（CGRP）也是如此，支持CGRP拮抗剂的发展，现在广泛用于患者。同样，垂体腺苷酸环化酶激活肽（PACAP）引起头痛和偏头痛。最近，PACAP抗体在2期试验中显示出抗偏头痛活性。由NO激活的第二信使的增加，CGRP和PACAP可有效诱导偏头痛。实验模型也已用于其他类型的头痛，并已与成像和生化研究相结合。它们还被用于药物测试和遗传研究。
结论：结论。人类偏头痛激发模型已经了解了偏头痛的信号机制，从而导致了新的药物和药物靶标。未来这些模型在图像中的使用-，生物化学和遗传研究以及在动物模型的进一步研究是有希望的。
方法：对参考文献列表的审查补充了对文献的广泛了解。
结果：早期研究使用的方法不是盲法。他们建议组胺和硝酸甘油（三硝酸甘油酯，GTN）可能会引起头痛和偏头痛。双盲的发展，安慰剂对照模型，对诱发性偏头痛使用明确的诊断标准是向前迈出的重要一步.GTN,一氧化氮（NO）的供体，在有和没有偏头痛的人中诱发头痛，以及偏头痛患者的偏头痛发作延迟。降钙素基因相关肽（CGRP）也是如此，支持CGRP拮抗剂的发展，现在广泛用于患者。同样，垂体腺苷酸环化酶激活肽（PACAP）引起头痛和偏头痛。最近，PACAP抗体在2期试验中显示出抗偏头痛活性。由NO激活的第二信使的增加，CGRP和PACAP可有效诱导偏头痛。实验模型也已用于其他类型的头痛，并已与成像和生化研究相结合。它们还被用于药物测试和遗传研究。
结论：结论。人类偏头痛激发模型已经了解了偏头痛的信号机制，从而导致了新的药物和药物靶标。未来这些模型在图像中的使用-，生物化学和遗传研究以及在动物模型的进一步研究是有希望的。
