Department of Molecular Physiology and Biophysics, University of Iowa Carver College of Medicine, University of Iowa, Iowa City, IA, United States.
Center for the Prevention and Treatment of Visual Loss, Iowa VA Medical Center, Iowa City, IA, United States.
Pain. 2018 Nov;159(11):2306-2317. doi: 10.1097/j.pain.0000000000001337.
Migraine is the third most common disease in the world (behind dental caries and tension-type headache) with an estimated global prevalence of 15%, yet its etiology remains poorly understood. Recent clinical trials have heralded the potential of therapeutic antibodies that block the actions of the neuropeptide calcitonin gene-related peptide (CGRP) or its receptor to prevent migraine. Calcitonin gene-related peptide is believed to contribute to trigeminal nerve hypersensitivity and photosensitivity in migraine, but a direct role in pain associated with migraine has not been established. In this study, we report that peripherally administered CGRP can act in a light-independent manner to produce spontaneous pain in mice that is manifested as a facial grimace. As an objective validation of the orbital tightening action unit of the grimace response, we developed a squint assay using a video-based measurement of the eyelid fissure, which confirmed a significant squint response after CGRP injection, both in complete darkness and very bright light. These indicators of discomfort were completely blocked by preadministration of a monoclonal anti-CGRP-blocking antibody. However, the nonsteroidal anti-inflammatory drug meloxicam failed to block the effect of CGRP. Interestingly, an apparent sex-specific response to treatment was observed with the antimigraine drug sumatriptan partially blocking the CGRP response in male, but not female mice. These results demonstrate that CGRP can induce spontaneous pain, even in the absence of light, and that the squint response provides an objective biomarker for CGRP-induced pain that is translatable to humans.
偏头痛是世界上第三常见的疾病（仅次于龋齿和紧张性头痛），估计全球患病率为 15%，但其病因仍知之甚少。最近的临床试验预示着治疗性抗体可能具有阻断降钙素基因相关肽（CGRP）或其受体作用以预防偏头痛的潜力。降钙素基因相关肽被认为有助于偏头痛三叉神经超敏和光敏感，但与偏头痛相关疼痛的直接作用尚未确定。在这项研究中，我们报告称，外周给予 CGRP 可以以非光依赖的方式在小鼠中产生自发性疼痛，表现为面部扭曲。作为扭曲反应的眶紧束动作单元的客观验证，我们开发了一种斜视测定法，使用基于视频的眼睑裂缝测量法，该方法在 CGRP 注射后确认了明显的斜视反应，无论是在完全黑暗还是非常明亮的光线下。这种不适的指标完全被预先给予的单克隆抗 CGRP 阻断抗体所阻断。然而，非甾体抗炎药美洛昔康未能阻断 CGRP 的作用。有趣的是，抗偏头痛药物舒马曲坦对治疗的反应表现出明显的性别特异性，部分阻断了雄性而不是雌性小鼠的 CGRP 反应。这些结果表明，CGRP 甚至可以在没有光的情况下引起自发性疼痛，而斜视反应为 CGRP 诱导的疼痛提供了一种客观的生物标志物，可转化为人类。
