The higher incidence of migraines in women compared with men has led to the inclusion of female animals in pain research models. However, the critical role of the hormonal cycle is frequently overlooked, despite its clear correlation with migraine occurrences. In this study, we show in a rat model of migraine induced by repeated dural infusions of an inflammatory soup (IS) that a second IS (IS2) injection performed in proestrus/estrus (PE, high estrogen) female rats evokes higher cephalic mechanical hypersensitivities than when performed in metestrus/diestrus (MD, low estrogen) or ovariectomized (OV) rats. This hypersensitivity induced by IS2 correlates with increased c-Fos expression in outer lamina II (IIo) neurons located in the periorbital projection area of the trigemino-cervical complex (TCC), in PE only. Four IS (IS4) repetition induced an enlargement of c-Fos expression in adjacent territories areas in PE, but not MD or OV animals. Unexpectedly, c-Fos expression in locus coeruleus neurons does not potentiate after IS2 or IS4 injections. To examine the impacts of the hormonal cycle on the physiology of lamina IIo TCC neurons, we performed whole-cell patch-clamp recordings. Second inflammatory soup depolarizes neurons in PE and MD but not in OV rats and enhances excitatory synaptic inputs in PE animals to a greater extent compared with MD and OV rats. These findings show that central TCC sensitization triggered by meningeal nociceptor activation and the resulting cephalic hypersensitivity are modulated by the estrous cycle. This highlights the crucial need to account for not just sex, but also the female estrous cycle in pain research.

中文翻译：

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发情周期调节慢性偏头痛雌性大鼠模型中的头部机械敏感性和三叉神经-宫颈复合体的敏化。


与男性相比，女性偏头痛的发生率更高，这导致女性动物被纳入疼痛研究模型。然而，尽管荷尔蒙周期与偏头痛的发生有明显的相关性，但它的关键作用经常被忽视。在这项研究中，我们在反复硬脑膜输注炎症汤 （IS） 诱导的偏头痛大鼠模型中表明，在发情前/发情期（PE，高雌激素）雌性大鼠中进行的第二次 IS （IS2） 注射比在睾丸/发情期（MD，低雌激素）或卵巢切除 （OV） 大鼠中进行的第二次 IS （IS2） 注射引起更高的头部机械超敏反应。这种由 IS2 诱导的超敏反应与位于三叉神经-颈椎复合体 （TCC） 眶周投影区域的外层 II （IIo） 神经元中 c-Fos 表达的增加相关，仅在 PE 中。4 次 IS （IS4） 重复诱导 PE 相邻区域 c-Fos 表达增加，但 MD 或 OV 动物没有。出乎意料的是，在 IS2 或 IS4 注射后，蓝斑神经元中的 c-Fos 表达不会增强。为了检查荷尔蒙周期对 IIo TCC 神经元层生理学的影响，我们进行了全细胞膜片钳记录。与 MD 和 OV 大鼠相比，Second inflammatory soup 使 PE 和 MD 大鼠的神经元去极化，但不使 OV 大鼠的神经元去极化，并在更大程度上增强 PE 动物的兴奋性突触输入。这些发现表明，由脑膜伤害感受器激活触发的中枢 TCC 敏化和由此产生的头部超敏反应受发情周期的调节。这凸显了在疼痛研究中不仅要考虑性别，还要考虑女性发情周期的迫切需要。