Primary headache conditions are frequently associated with multiple sclerosis (MS), but the mechanism that triggers or worsens headaches in patients with MS is poorly understood. We previously showed that the proalgesic transient receptor potential ankyrin 1 (TRPA1) mediates hind paw mechanical and cold allodynia in a relapsing–remitting experimental autoimmune encephalomyelitis (RR-EAE) model in mice. Here, we investigated the development of periorbital mechanical allodynia (PMA) in RR-EAE, a hallmark of headache, and if TRPA1 contributed to this response. RR-EAE induction by injection of the myelin oligodendrocyte peptide fragment_35-55 (MOG_35-55) and Quillaja A adjuvant (Quil A) in C57BL/6J female mice elicited a delayed and sustained PMA. The PMA at day 35 after induction was reduced by the calcitonin gene–related peptide receptor antagonist (olcegepant) and the serotonin 5-HT1_B/D receptor agonist (sumatriptan), 2 known antimigraine agents. Genetic deletion or pharmacological blockade of TRPA1 attenuated PMA associated with RR-EAE. The levels of oxidative stress biomarkers (4-hydroxynonenal and hydrogen peroxide, known TRPA1 endogenous agonists) and superoxide dismutase and NADPH oxidase activities were increased in the trigeminal ganglion of RR-EAE mice. Besides, the treatment with antioxidants (apocynin or α-lipoic acid) attenuated PMA. Thus, the results of this study indicate that TRPA1, presumably activated by endogenous agonists, evokes PMA in a mouse model of relapsing–remitting MS.

原发性头痛通常与多发性硬化症 (MS) 相关，但引发或加重多发性硬化症患者头痛的机制尚不清楚。我们之前表明，在小鼠复发缓解型实验性自身免疫性脑脊髓炎（RR-EAE）模型中，促痛瞬时受体电位锚蛋白1（TRPA1）介导后爪​​机械性和冷异常性疼痛。在这里，我们研究了 RR-EAE 中眶周机械异常性疼痛 (PMA) 的发展情况（头痛的标志），以及 TRPA1 是否促成了这种反应。通过在 C57BL/6J 雌性小鼠中注射髓鞘少突胶质细胞肽片段_35-55 (MOG _{35-55 ) 和 Quillaja A 佐剂 (Quil A) 诱导 RR-EAE，引发延迟且持续的 PMA。诱导后第 35 天，降钙素基因相关肽受体拮抗剂（olcegepant）和血清素 5-HT1 B/D}受体激动剂（舒马曲坦）（两种已知的抗偏头痛药物）可降低 PMA 。TRPA1 的基因缺失或药理学阻断可减弱与 RR-EAE 相关的 PMA。RR-EAE 小鼠三叉神经节中氧化应激生物标志物（4-羟基壬烯醛和过氧化氢，已知的 TRPA1 内源性激动剂）以及超氧化物歧化酶和NADPH 氧化酶活性的水平增加。此外，抗氧化剂（夹竹桃麻素或α-硫辛酸）治疗可减弱PMA。因此，本研究的结果表明，TRPA1（可能被内源性激动剂激活）在复发缓解型多发性硬化症小鼠模型中诱发 PMA。