Department of Health Sciences, Clinical Pharmacology Unit, University of Florence, Florence, Italy Headache Center, Florence University Hospital, Florence, Italy Department of Chemistry "U. Schiff", University of Florence, Florence, Italy King's College, London, UK Department of Pharmacology, University of Arizona, Tucson, AZ, USA Department of Pharmaceutical Sciences, University of Eastern Piedmont, Novara, Italy Pharmacology Department, Chiesi Farmaceutici SpA, Parma, Italy.
Pain. 2013 Dec;154(12):2750-2758. doi: 10.1016/j.pain.2013.08.002. Epub 2013 Aug 8.
Although feverfew has been used for centuries to treat pain and headaches and is recommended for migraine treatment, the mechanism for its protective action remains unknown. Migraine is triggered by calcitonin gene-related peptide (CGRP) release from trigeminal neurons. Peptidergic sensory neurons express a series of transient receptor potential (TRP) channels, including the ankyrin 1 (TRPA1) channel. Recent findings have identified agents either inhaled from the environment or produced endogenously that are known to trigger migraine or cluster headache attacks, such as TRPA1 simulants. A major constituent of feverfew, parthenolide, may interact with TRPA1 nucleophilic sites, suggesting that feverfew's antimigraine effect derives from its ability to target TRPA1. We found that parthenolide stimulates recombinant (transfected cells) or natively expressed (rat/mouse trigeminal neurons) TRPA1, where it, however, behaves as a partial agonist. Furthermore, in rodents, after initial stimulation, parthenolide desensitizes the TRPA1 channel and renders peptidergic TRPA1-expressing nerve terminals unresponsive to any stimulus. This effect of parthenolide abrogates nociceptive responses evoked by stimulation of peripheral trigeminal endings. TRPA1 targeting and neuronal desensitization by parthenolide inhibits CGRP release from trigeminal neurons and CGRP-mediated meningeal vasodilatation, evoked by either TRPA1 agonists or other unspecific stimuli. TRPA1 partial agonism, together with desensitization and nociceptor defunctionalization, ultimately resulting in inhibition of CGRP release within the trigeminovascular system, may contribute to the antimigraine effect of parthenolide.
尽管小白菊被用于治疗疼痛和头痛已有几个世纪的历史，并且被推荐用于偏头痛治疗，但它的保护作用机制仍不清楚。偏头痛是由三叉神经神经元释放降钙素基因相关肽（CGRP）引起的。肽能感觉神经元表达一系列瞬时受体电位（TRP）通道，包括锚蛋白 1（TRPA1）通道。最近的研究发现，一些已知会引发偏头痛或丛集性头痛发作的环境吸入或内源性物质，如 TRPA1 模拟物。小白菊的主要成分小白菊内酯可能与 TRPA1 的亲核部位相互作用，这表明小白菊的抗偏头痛作用源于其靶向 TRPA1 的能力。我们发现小白菊内酯刺激重组（转染细胞）或天然表达（大鼠/小鼠三叉神经神经元）的 TRPA1，在那里它表现为部分激动剂。此外，在啮齿动物中，小白菊内酯在初始刺激后使 TRPA1 通道脱敏，并使表达肽能的 TRPA1 神经末梢对任何刺激无反应。小白菊内酯的这种作用消除了外周三叉神经末梢刺激引起的伤害性反应。TRPA1 靶向和小白菊内酯引起的神经元脱敏抑制了三叉神经神经元释放 CGRP 和 CGRP 介导的脑膜血管扩张，这是由 TRPA1 激动剂或其他非特异性刺激引起的。TRPA1 的部分激动作用，加上脱敏和伤害感受器失能，最终导致三叉血管系统中 CGRP 释放的抑制，这可能有助于小白菊内酯的抗偏头痛作用。
