School of Behavioral and Brain Sciences, The University of Texas at Dallas, Richardson, TX, USA.
Cephalalgia. 2021 Feb;41(2):237-246. doi: 10.1177/0333102420970514. Epub 2020 Nov 17.
Migraine attacks are often triggered by normally innocuous stimuli, suggesting that sensitization within the nervous system is present. One mechanism that may contribute to neuronal sensitization in this context is translation regulation of new protein synthesis. The goal of this study was to determine whether protein synthesis contributes to behavioral responses and priming in preclinical models of migraine.
Mice received a dural injection of interleukin-6 in the absence or presence of the protein synthesis inhibitor anisomycin or the translation initiation inhibitor 4EGI-1 and were tested for facial hypersensitivity. Upon returning to baseline, mice were given a second, non-noxious dural injection of pH 7.0 to test for priming. Additionally, mice lacking phosphorylation of mRNA cap-binding protein eIF4E received dural interleukin-6 or were subjected to repeated restraint stress and then tested for facial hypersensitivity. After returning to baseline, mice were given either dural pH 7.0 or a systemic sub-threshold dose of the nitric oxide donor sodium nitroprusside and tested for priming.
Dural injection of interleukin-6 in the presence of anisomycin or 4EGI-1 or in mice resulted in the partial attenuation of acute facial hypersensitivity and complete block of hyperalgesic priming. Additionally, hyperalgesic priming following repeated restraint stress was blocked in mice.
These studies show that protein synthesis regulated by activity-dependent translation is critical to the development of priming in two preclinical models of migraine. This suggests that targeting the regulation of protein synthesis may be a novel approach for new migraine treatment strategies.
偏头痛发作通常由无害的刺激引发，这表明神经系统内存在敏化现象。在这种情况下，可能有助于神经元敏化的一种机制是新蛋白质合成的翻译调控。本研究的目的是确定蛋白质合成是否有助于偏头痛临床前模型中的行为反应和引发。
在不存在或存在蛋白质合成抑制剂 anisomycin 或翻译起始抑制剂 4EGI-1 的情况下，向小鼠硬膜内注射白细胞介素-6，并测试面部过敏反应。回到基线后，给予第二次非伤害性硬膜内 pH7.0 注射以测试引发。此外，还对缺乏 mRNA 帽结合蛋白 eIF4E 磷酸化的小鼠进行硬膜内白细胞介素-6 注射或进行重复束缚应激，然后测试面部过敏反应。回到基线后，给予硬膜内 pH7.0 或全身亚阈值剂量的一氧化氮供体硝普钠，并进行引发测试。
在 anisomycin 或 4EGI-1 存在下或在小鼠中硬膜内注射白细胞介素-6 会部分减轻急性面部过敏反应，并完全阻断痛觉过敏引发。此外，在重复束缚应激后，痛觉过敏引发也被阻断在小鼠中。
这些研究表明，活性依赖性翻译调节的蛋白质合成对于两种偏头痛临床前模型中的引发发展至关重要。这表明靶向蛋白质合成的调节可能是治疗偏头痛的新策略。
