Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents
Prevention of stress- or nitric oxide donor-induced medication overuse headache by a calcitonin gene-related peptide antibody in rodents
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DOI：
10.1177/0333102416650702
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发表时间：
2017-05-01
期刊：
影响因子：
4.9
通讯作者：
Porreca, Frank
中科院分区：
文献类型：
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作者：
Kopruszinski, Caroline Machado;Xie, Jennifer Yanhua;Porreca, Frank
目的：本研究的目的是在无损伤的临床前模型中确定降钙素基因相关肽（CGRP）在诱导药物过度使用性头痛（MOH）相关偏头痛中的作用。方法：对大鼠进行为期7天的急性偏头痛治疗，包括舒马曲坦和吗啡。在另外14天的无药期后，大鼠暴露于假定的偏头痛触发因素，包括明亮光应激（BLS）或一氧化氮（NO）供体，存在或不存在TEV48125（一种完全人源化的CGRP抗体）。皮肤异常性疼痛（CA）作为结局指标，并测量CGRP血液和脑脊液（CSF）水平。结果：BLS和NO供体攻击在先前用过舒马普坦或吗啡治疗的大鼠中选择性地诱发了延迟的、持久的CA。与生理盐水对照相比，先前暴露于舒马曲坦的动物，BLS使血浆中CGRP显著增加，但脑脊液中没有CGRP。TEV48125不改变基线触觉阈值或产生行为副作用，但显著抑制先前使用舒马普坦或吗啡的动物的BLS和NO供体诱导的CA；不结合CGRP的同型控制蛋白没有作用。解释：这些数据表明，急性偏头痛药物可能通过cgrp依赖机制促进易感个体的MOH，抗cgrp抗体可能是治疗MOH的有用临床策略。
Objective: The objective of this study was the determination of the role of calcitonin gene-related peptide (CGRP) in the induction of medication overuse headache (MOH)-related migraine in an injury-free preclinical model.Methods: Rats were primed by a 7-day period of exposure to acute migraine therapies including sumatriptan and morphine. After an additional 14-day drug-free period, rats were exposed to putative migraine triggers including bright light stress (BLS) or nitric oxide (NO) donor in the presence or absence of TEV48125, a fully humanized CGRP antibody. Cutaneous allodynia (CA) was used as an outcome measure and CGRP blood and cerebrospinal fluid (CSF) levels were measured.Results: BLS and NO donor challenge evoked delayed, long-lasting CA selectively in rats that were previously treated with sumatriptan or morphine. BLS produced a significant increase in CGRP in the plasma, but not CSF, in animals that were previously exposed to sumatriptan compared to saline controls. TEV48125 did not modify baseline tactile thresholds or produce behavioral side effects, but significantly inhibited both BLS- and NO donor-induced CA in animals that were previously primed with sumatriptan or morphine; an isotype control protein that does not bind CGRP had no effect.Interpretation: These data suggest that acute migraine medications may promote MOH in susceptible individuals through CGRP-dependent mechanisms and that anti-CGRP antibodies may be a useful clinical strategy for the treatment of MOH.