The effect of sex and estrus cycle stage on optogenetic spreading depression induced migraine-like pain phenotypes.
The effect of sex and estrus cycle stage on optogenetic spreading depression induced migraine-like pain phenotypes.
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DOI：
10.1186/s10194-023-01621-1
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发表时间：
2023-07-19
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--
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偏头痛在女性中更为普遍，这增加了性激素和性腺激素调节偏头痛的可能性。我们最近证实，微创的光遗传扩散性去极化(OPTO-SD)可以引起强烈的眶周痛觉异常。这项研究的目的是验证这一假设，即光-SD诱导的偏头痛样疼痛行为在雌性中更差，并在发情周期中变化。在雄性和雌性成年Thy1-ChR2-YFP转基因小鼠中诱导出单一或重复的光-SDS。用von Frey单丝测试眼眶周围机械性异位痛觉。在增加光照强度的情况下，老鼠的鬼脸也被检测，以量化自发的不适和厌恶光线的行为。行为测试结束后，取阴道涂片进行动情周期分期。使用一组男性和女性队列进行了多变量回归分析，以检验自变量对眶周痛的影响。与假刺激相比，OPTO-SD预测眼眶周围阈值更低(p <； 0.0001)。此外，与男性相比，女性预测眼眶周围阈值较低(p = 0.011)。随着时间的推移，动物倾向于从视觉-SD异常痛觉中恢复，而性别与时间之间存在显著的交互作用(交互作用p = 0.030)，因为雌性动物恢复的时间往往更长(p = 0.020)。动情前期、动情期(PE)和动情期、间情期(MD)分别代表雌二醇相对于孕酮的高或低循环。多变量回归分析显示发情周期(p = 0.015)对眼眶周围阈值有影响。在假手术组，PE阈值低于MD组。然而，OPTO-SD与发情周期之间没有交互作用(p = 0.364)。在增加光线强度的情况下，还检查了鬼脸评分。光刺激(p <； 0.0001)、光照强度(p = 0.001)和发情周期(p = 0.024)对表情的影响不存在交互作用(三因素方差分析)。雌性期和发情期的雌二醇相对孕酮水平较高，三叉神经痛觉阈值较低，光敏性增强。在雌性中，无论发情期如何，光敏SD都会增加疼痛行为和光敏性。
Migraine is more prevalent in females, raising the possibility that sex and gonadal hormones modulate migraine. We recently demonstrated that minimally invasive optogenetic spreading depolarization (opto-SD) elicits robust periorbital allodynia. The objective of this study was to test the hypothesis that opto-SD induced migraine-like pain behavior is worse in females and varies during the estrus cycle. Single or repeated opto-SDs were induced in male and female adult Thy1-ChR2-YFP transgenic mice. Von Frey monofilaments were used to test periorbital mechanical allodynia. Mouse grimace was also examined under increasing light intensity to quantify spontaneous discomfort and light-aversive behavior. Vaginal smears were obtained for estrus cycle staging at the end of behavioral testing. A multi-variable regression analysis was performed using a male and female cohort to test the effect of independent variables on periorbital allodynia. Opto-SD predicted lower periorbital thresholds as compared with sham stimulation (p < 0.0001). Additionally, female sex predicted lower periorbital thresholds compared with males (p = 0.011). There were significant interactions between opto-SD and time (interaction p = 0.030) as animals tended to recover from opto-SD allodynia over time, and between sex and time (p = 0.020) as females tended to take longer to recover. Proestrus, estrus (PE) and metestrus, diestrus (MD) stages were combined to represent high versus low circulating estradiol relative to progesterone, respectively. Multi-variable regression revealed an effect of estrus cycle (p = 0.015) on periorbital thresholds. In the sham group, PE had lower thresholds than MD. However, there was no interaction between opto-SD and the estrus cycle (p = 0.364). Grimace scores were also examined at incremental light intensities. There was an effect of opto-SD (p < 0.0001), light intensity (p = 0.001) and estrus cycle (p = 0.024) on grimace without interaction among them (three-way ANOVA). Female sex and estrus stages with high circulating estradiol relative to progesterone lower trigeminal pain thresholds and augment photosensitivity. In females, opto-SD increased pain behavior and photosensitivity irrespective of the estrus stage.
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