Department of Clinical and Experimental Research, Glostrup Research Institute, Copenhagen University Hospital, Rigshospitalet-Glostrup, Nordstjernevej 42, 2600, Glostrup, Denmark.
CNS Drugs. 2019 Jun;33(6):525-537. doi: 10.1007/s40263-019-00630-6.
Migraine is a strongly disabling disease characterized by a unilateral throbbing headache lasting for up to 72 h for each individual attack. There have been many theories on the pathophysiology of migraine throughout the years. Currently, the neurovascular theory dominates, suggesting clear involvement of the trigeminovascular system. The most recent data show that a migraine attack most likely originates in the hypothalamus and activates the trigeminal nucleus caudalis (TNC). Although the mechanisms are unknown, activation of the TNC leads to peripheral release of calcitonin gene-related protein (CGRP), most likely from C-fibers. During the past year monoclonal antibodies against CGRP or the CGRP receptor have emerged as the most promising targets for migraine therapy, and at the same time established the strong involvement of CGRP in the pathophysiology of migraine. The viewpoint presented here focuses further on the activation of the CGRP receptor on the sensory Aδ-fiber, leading to the sensation of pain. The CGRP receptor activates adenylate cyclase, which leads to an increase in cyclic adenosine monophosphate (cAMP). We hypothesize that cAMP activates the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, triggering an action potential sensed as pain. The mechanisms behind migraine pain on a molecular level, particularly their importance to cAMP, provide clues to potential new anti-migraine targets. In this article we focus on the development of targets related to the CGRP system, and further include novel targets such as the pituitary adenylate cyclase-activating peptide (PACAP) system, the serotonin 5-HT receptor, purinergic receptors, HCN channels, adenosine triphosphate-sensitive potassium channels (K), and the glutaminergic system.
偏头痛是一种严重致残的疾病，其特征为每个发作期单侧搏动性头痛，持续时间长达 72 小时。多年来，人们提出了许多偏头痛发病机制的理论。目前，神经血管学说占主导地位，表明三叉神经血管系统明显参与其中。最新数据显示，偏头痛发作很可能起源于下丘脑，并激活三叉神经尾核（TNC）。尽管其机制尚不清楚，但 TNC 的激活导致降钙素基因相关肽（CGRP）的外周释放，很可能来自 C 纤维。在过去的一年中，针对 CGRP 或 CGRP 受体的单克隆抗体已成为偏头痛治疗最有希望的靶点，同时也证实了 CGRP 强烈参与偏头痛的病理生理学。本文进一步聚焦于 CGRP 受体在感觉 Aδ 纤维上的激活，导致疼痛感觉。CGRP 受体激活腺苷酸环化酶，导致环磷酸腺苷（cAMP）增加。我们假设 cAMP 激活超极化激活环核苷酸门控（HCN）通道，引发被感知为疼痛的动作电位。偏头痛疼痛的分子水平机制，特别是它们对 cAMP 的重要性，为潜在的新抗偏头痛靶点提供了线索。本文重点介绍与 CGRP 系统相关的靶点的开发，并进一步包括新的靶点，如垂体腺苷酸环化酶激活肽（PACAP）系统、5-羟色胺 5-HT 受体、嘌呤能受体、HCN 通道、三磷酸腺苷敏感钾通道（K）和谷氨酸能系统。
