1 Danish Headache Centre and Department of Neurology, Glostrup Hospital, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.
Brain. 2014 Mar;137(Pt 3):779-94. doi: 10.1093/brain/awt369. Epub 2014 Feb 5.
Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide are structurally and functionally closely related but show differences in migraine-inducing properties. Mechanisms responsible for the difference in migraine induction are unknown. Here, for the first time, we present a head-to-head comparison study of the immediate and long-lasting observations of the migraine-inducing, arterial, physiological and biochemical responses comparing PACAP38 and vasoactive intestinal polypeptide. In a double-blind crossover study 24 female migraine patients without aura were randomly allocated to intravenous infusion of PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We recorded incidence of migraine during and after infusion (0-24 h). Magnetic resonance angiography of selected extra- and intracranial arteries, blood samples (plasma PACAP38 and vasoactive intestinal polypeptide and serum tryptase), and vital signs (blood pressure, heart rate, respiratory frequency, and end-tidal pressure of CO2) was recorded before and up to 5 h after infusion. Twenty-two patients [mean age 24 years (range 19-36)] completed the study on both days. Sixteen patients (73%) reported migraine-like attacks after PACAP38 and four after vasoactive intestinal polypeptide (18%) infusion (P = 0.002). Three of four patients, who reported migraine-like attacks after vasoactive intestinal polypeptide, also reported attacks after PACAP38. Both peptides induced marked dilatation of the extracranial (P < 0.05), but not intracranial arteries (P > 0.05). PACAP38-induced vasodilatation was longer lasting (>2 h), whereas vasoactive intestinal polypeptide-induced dilatation was normalized after 2 h. We recorded elevated plasma PACAP38 at 1 h after the start of PACAP38 infusion only in those patients who later reported migraine attacks. Blood levels of vasoactive intestinal polypeptide and tryptase were unchanged after PACAP38 infusion. In conclusion, PACAP38-induced migraine was associated with sustained dilatation of extracranial arteries and elevated plasma PACAP38 before onset of migraine-like attacks. PACAP38 has a much higher affinity for the PAC1 receptor and we therefore suggest that migraine induction by PACAP38 may be because of activation of the PAC1 receptor, which may be a future anti-migraine drug target.
垂体腺苷酸环化酶激活肽-38（PACAP38）和血管活性肠肽在结构和功能上密切相关，但在偏头痛诱导特性上存在差异。导致这种偏头痛诱导差异的机制尚不清楚。在这里，我们首次进行了一项头对头比较研究，比较了 PACAP38 和血管活性肠肽在诱导偏头痛、动脉、生理和生化反应方面的即时和长期观察结果。在一项双盲交叉研究中，24 名无先兆偏头痛女性患者被随机分为两组，分别静脉输注 PACAP38（10 pmol/kg/min）或血管活性肠肽（8 pmol/kg/min），输注时间为 20 分钟。我们记录了输注期间和输注后 0-24 小时内偏头痛的发作情况。在输注前和输注后 5 小时内，对选定的颅内外动脉进行磁共振血管造影，采集血液样本（血浆 PACAP38 和血管活性肠肽以及血清胰蛋白酶原）和生命体征（血压、心率、呼吸频率和 CO2 呼气末压）。22 名患者[平均年龄 24 岁（19-36 岁）]在两天内均完成了研究。16 名患者（73%）在 PACAP38 输注后报告偏头痛样发作，4 名患者在血管活性肠肽输注后报告偏头痛样发作（18%）（P = 0.002）。在血管活性肠肽输注后报告偏头痛样发作的 4 名患者中，有 3 名也在 PACAP38 输注后报告发作。两种肽均引起颅外动脉显著扩张（P < 0.05），但颅内动脉无明显扩张（P > 0.05）。PACAP38 诱导的血管扩张持续时间较长（>2 小时），而血管活性肠肽诱导的扩张在 2 小时后恢复正常。我们仅在随后报告偏头痛发作的患者中观察到，在 PACAP38 输注开始后 1 小时，血浆 PACAP38 水平升高。PACAP38 输注后，血管活性肠肽和胰蛋白酶原的血液水平没有变化。总之，PACAP38 诱导的偏头痛与颅外动脉持续扩张和偏头痛样发作前血浆 PACAP38 升高有关。PACAP38 对 PAC1 受体具有更高的亲和力，因此我们认为 PACAP38 诱导偏头痛可能是因为激活了 PAC1 受体，这可能是未来抗偏头痛药物的靶点。
