Blumenfeld Andrew, Durham Paul L, Feoktistov Alexander, Hay Debbie L, Russo Andrew F, Turner Ira
The Headache Center of Southern California, The Neurology Center, Carlsbad, CA, USA.
Department of Biology, Center for Biomedical and Life Sciences, Missouri State University, Springfield, MO, USA.
Neurol Ther. 2021 Dec;10(2):469-497. doi: 10.1007/s40120-021-00250-7. Epub 2021 Jun 2.
Migraine involves brain hypersensitivity with episodic dysfunction triggered by behavioral or physiological stressors. During an acute migraine attack the trigeminal nerve is activated (peripheral sensitization). This leads to central sensitization with activation of the central pathways including the trigeminal nucleus caudalis, the trigemino-thalamic tract, and the thalamus. In episodic migraine the sensitization process ends with the individual act, but with chronic migraine central sensitization may continue interictally. Increased allostatic load, the consequence of chronic, repeated exposure to stressors, leads to central sensitization, lowering the threshold for future neuronal activation (hypervigilance). Ostensibly innocuous stressors are then sufficient to trigger an attack. Medications that reduce sensitization may help patients who are hypervigilant and help to balance allostatic load. Acute treatments and drugs for migraine prevention have traditionally been used to reduce attack duration and frequency. However, since many patients do not fully respond, an unmet treatment need remains. Calcitonin gene-related peptide (CGRP) is a vasoactive neuropeptide involved in nociception and in the sensitization of peripheral and central neurons of the trigeminovascular system, which is implicated in migraine pathophysiology. Elevated CGRP levels are associated with dysregulated signaling in the trigeminovascular system, leading to maladaptive responses to behavioral or physiological stressors. CGRP may, therefore, play a key role in the underlying pathophysiology of migraine. Increased understanding of the role of CGRP in migraine led to the development of small-molecule antagonists (gepants) and monoclonal antibodies (mAbs) that target either CGRP or the receptor (CGRP-R) to restore homeostasis, reducing the frequency, duration, and severity of attacks. In clinical trials, US Food and Drug Administration-approved anti-CGRP-R/CGRP mAbs were well tolerated and effective as preventive migraine treatments. Here, we explore the role of CGRP in migraine pathophysiology and the use of gepants or mAbs to suppress CGRP-R signaling via inhibition of the CGRP ligand or receptor.
偏头痛涉及大脑超敏反应，由行为或生理应激源引发发作性功能障碍。在急性偏头痛发作期间，三叉神经被激活（外周敏化）。这会导致中枢敏化，激活包括三叉神经尾侧核、三叉丘脑束和丘脑在内的中枢通路。在发作性偏头痛中，敏化过程随着单次发作而结束，但在慢性偏头痛中，中枢敏化可能在发作间期持续存在。慢性、反复暴露于应激源导致的应激负荷增加会引发中枢敏化，降低未来神经元激活的阈值（过度警觉）。看似无害的应激源随后就足以引发发作。降低敏化的药物可能有助于过度警觉的患者，并有助于平衡应激负荷。传统上，用于偏头痛预防的急性治疗药物和药物可减少发作持续时间和频率。然而，由于许多患者并未完全缓解，仍存在未满足的治疗需求。降钙素基因相关肽（CGRP）是一种血管活性神经肽，参与伤害感受以及三叉神经血管系统外周和中枢神经元的敏化，而该系统与偏头痛病理生理学有关。CGRP水平升高与三叉神经血管系统信号失调有关，导致对行为或生理应激源的适应不良反应。因此，CGRP可能在偏头痛的潜在病理生理学中起关键作用。对CGRP在偏头痛中作用的深入了解促使了小分子拮抗剂（gepants）和单克隆抗体（mAbs）的研发，这些药物靶向CGRP或其受体（CGRP-R）以恢复内环境稳定，减少发作的频率、持续时间和严重程度。在临床试验中，美国食品药品监督管理局批准的抗CGRP-R/CGRP单克隆抗体耐受性良好，作为偏头痛预防性治疗有效。在此，我们探讨CGRP在偏头痛病理生理学中的作用，以及通过抑制CGRP配体或受体来抑制CGRP-R信号传导的gepants或单克隆抗体的应用。
