A male-specific mechanism of meningeal nociceptor sensitization promoting migraine headache.

IF 5 2区医学 Q1 CLINICAL NEUROLOGY

Cephalalgia Pub Date : 2024-09-01 DOI:10.1177/03331024241281493

Caroline M Kopruszinski, Grace Lee, Laurent K Martin, Kara R Barber, Aubin Moutal, David W Dodick, Edita Navratilova, Frank Porreca

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Abstract

Background: We wished to explore possible sexual dimorphism in mechanisms sensitizing or activating meningeal nociceptors that can promote the headache phase of migraine.

Methods: 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.

Results: 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.

Conclusions: 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.

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促进偏头痛的脑膜痛觉感受器敏感化的男性特异性机制。

背景：我们希望探索使脑膜痛觉感受器敏感或激活的机制中可能存在的性双态性，这种机制可促进偏头痛的头痛阶段：方法：雄性和雌性 C57BL6J 小鼠接受硬膜上奥曲肽 B 和炎症介质鸡尾酒（IM）治疗，并记录偏头痛样疼痛行为和畏光症状。评估了三叉神经节（TG）中奥曲肽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。用贴片钳电生理学方法评估了奥列克辛 B 诱导的 TG 细胞兴奋性。鼻内递送 CRISPR/Cas9 质粒用于编辑 TG 中 OX2R 的表达：结果：硬膜外奥曲肽B可诱导偏头痛样疼痛行为、畏光和TNC ERK磷酸化增加，且仅在雄性动物中发生。用硬膜上奥曲肽受体双重拮抗剂苏伐生阻断奥曲肽信号传导，可防止但不能逆转硬膜上 IM 鸡尾酒诱导的雄性偏头痛样疼痛。OX2R 在雄性 TG 中的表达量更高，而奥曲肽 B 能提高雄性 TG 神经元的兴奋性。鼻内 OX2R CRISPR/Cas9 减少了男性 TG 受体的表达和奥曲肽 B 诱导的 TNC ERK 磷酸化，并预防了硬膜上奥曲肽 B 诱导的偏头痛样疼痛：我们的研究揭示了奥曲肽 B/OX2R 信号介导的 TG 感受器敏感化和偏头痛样疼痛行为的男性特异性机制。三叉神经痛觉感受器敏化和激活的性别双态机制为通过考虑患者性别来改善患者预后提供了机会，并可能影响临床试验的设计和解释。

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来源期刊

Cephalalgia 医学-临床神经学

CiteScore

10.10

自引率

6.10%

发文量

108

审稿时长

4-8 weeks

期刊介绍： Cephalalgia contains original peer reviewed papers on all aspects of headache. The journal provides an international forum for original research papers, review articles and short communications. Published monthly on behalf of the International Headache Society, Cephalalgia''s rapid review averages 5 ½ weeks from author submission to first decision.