The role of the major estrogen estradiol (E2) on orofacial pain conditions remains controversial with studies reporting both a pronociceptive and antinociceptive role of E2. E2 modulation of peripheral serotonergic activity may be one mechanism underlying the female prevalence of orofacial pain disorders. We recently reported that female rats in proestrus and estrus exhibit greater serotonin (5HT)-evoked orofacial nocifensive behaviors compared with diestrus and male rats. Further coexpression of 5HT_2A receptor mRNA in nociceptive trigeminal sensory neurons that express transient receptor potential vanilloid 1 ion channels contributes to pain sensitization. E2 may exacerbate orofacial pain through 5HT-sensitive trigeminal nociceptors, but whether low or high E2 contributes to orofacial pain and by what mechanism remains unclear. We hypothesized that steady-state exposure to a proestrus level of E2 exacerbates 5HT-evoked orofacial nocifensive behaviors in female rats, explored the transcriptome of E2-treated female rats, and determined which E2 receptor contributes to sensitization of female trigeminal sensory neurons. We report that a diestrus level of E2 is protective against 5HT-evoked orofacial pain behaviors, which increase with increasing E2 concentrations, and that E2 differentially alters several pain genes in the trigeminal ganglia. Furthermore, E2 receptors coexpressed with 5HT_2A and transient receptor potential vanilloid 1 and enhanced capsaicin-evoked signaling in the trigeminal ganglia through estrogen receptor α. Overall, our data indicate that low, but not high, physiological levels of E2 protect against orofacial pain, and we provide evidence that estrogen receptor α receptor activation, but not others, contributes to sensitization of nociceptive signaling in trigeminal sensory neurons.

主要雌激素雌二醇 (E2) 对口面部疼痛的作用仍存在争议，有研究报道 E2 具有促痛和抗痛作用。 E2 对外周血清素能活性的调节可能是女性口面部疼痛疾病患病率的机制之一。我们最近报道，与发情间期和雄性大鼠相比，雌性大鼠在发情前期和发情期表现出更强的血清素（5HT）诱发的口面部伤害行为。 5HT _2A受体 mRNA 在表达瞬时受体电位香草酸 1 离子通道的伤害性三叉神经感觉神经元中的进一步共表达有助于疼痛敏化。 E2 可能通过 5HT 敏感的三叉神经伤害感受器加剧口面部疼痛，但低或高 E2 是否会导致口面部疼痛以及通过什么机制仍不清楚。我们假设稳态暴露于发情前期水平的 E2 会加剧雌性大鼠中 5HT 诱发的口面部伤害行为，探索了 E2 治疗的雌性大鼠的转录组，并确定了哪种 E2 受体有助于雌性三叉神经感觉神经元的敏化。我们报告说，发情间期的 E2 水平可以预防 5HT 引起的口面部疼痛行为，这种行为随着 E2 浓度的增加而增加，并且 E2 差异性地改变三叉神经节中的几个疼痛基因。此外，E2 受体与 5HT _2A和瞬时受体电位香草酸 1 共表达，并通过雌激素受体 α 增强三叉神经节中辣椒素诱发的信号传导。 总体而言，我们的数据表明，低但不高的 E2 生理水平可以预防口面部疼痛，并且我们提供的证据表明，雌激素受体 α 受体激活（而不是其他受体）有助于三叉神经感觉神经元中伤害性信号的敏化。