Department of Pharmacology, University of Arizona College of Medicine, Tucson, AZ, USA.
Department of Anesthesiology, University of Arizona College of Medicine, Tucson, AZ, USA.
Cephalalgia. 2024 Sep;44(9):3331024241281493. doi: 10.1177/03331024241281493.
We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine.
Male and female C57BL6J mice received either supradural orexin B and an inflammatory mediator cocktail (IM) with migraine-like pain behaviors and photophobia recorded. Expression of orexin 2 receptor (OX2R) in trigeminal ganglion (TG) and phosphorylated extracellular signal-regulated kinases (ERK) levels in trigeminal nucleus caudalis (TNC) were evaluated. Orexin B-induced excitability of TG cells was assessed with patch-clamp electrophysiology. Intranasal delivery of CRISPR/Cas9 plasmids was used to edit the expression of OX2R in the TG.
Supradural orexin B induced migraine-like pain behaviors, photophobia and increased TNC ERK phosphorylation exclusively in males. Blockade of orexin signaling with supradural suvorexant, a dual orexin receptor antagonist, prevented, but did not reverse, migraine-like pain in males induced by supradural IM cocktail. OX2R expression was higher in male TG and orexin B increased TG neuron excitability in males. Intranasal OX2R CRISPR/Cas9 reduced TG receptor expression and orexin B-induced TNC ERK phosphorylation and prevented migraine-like pain induced by supradural orexin B in males.
Our studies reveal a male-specific mechanism of TG nociceptor sensitization and migraine-like pain behavior mediated by orexin B/OX2R signaling. Sexually dimorphic mechanisms of trigeminal nociceptor sensitization and activation offer opportunities to improve patient outcomes by considering patient sex and may influence clinical trial design and interpretation.
我们希望探索敏化或激活脑膜伤害感受器的可能性别二态机制，这些机制可能促进偏头痛的头痛阶段。
雄性和雌性 C57BL6J 小鼠接受硬膜外促食欲素 B 和炎症介质鸡尾酒（具有偏头痛样疼痛行为和畏光的混合物），并记录其表现。评估三叉神经节（TG）中促食欲素 2 受体（OX2R）的表达和三叉神经尾核（TNC）中磷酸化细胞外信号调节激酶（ERK）的水平。用膜片钳电生理学评估促食欲素 B 诱导的 TG 细胞兴奋性。使用 CRISPR/Cas9 质粒的鼻内传递来编辑 TG 中 OX2R 的表达。
硬膜外促食欲素 B 仅在雄性中诱导偏头痛样疼痛行为、畏光和增加 TNC ERK 磷酸化。硬膜外苏沃雷生（一种双重食欲素受体拮抗剂）阻断食欲素信号可预防，但不能逆转雄性中由硬膜外 IM 鸡尾酒引起的偏头痛样疼痛。雄性 TG 中的 OX2R 表达更高，促食欲素 B 增加雄性 TG 神经元的兴奋性。鼻内 OX2R CRISPR/Cas9 减少 TG 受体表达和促食欲素 B 诱导的 TNC ERK 磷酸化，并防止雄性中由硬膜外促食欲素 B 引起的偏头痛样疼痛。
我们的研究揭示了 TG 伤害感受器敏化和促食欲素 B/OX2R 信号介导的偏头痛样疼痛行为的男性特异性机制。三叉神经伤害感受器敏化和激活的性别二态机制为通过考虑患者性别改善患者预后提供了机会，并且可能影响临床试验设计和解释。
