Raquin Marie, Mrad Yara, Zkim Mohamed A, Dallel Radhouane, Ranchon-Cole Isabelle, Alba-Delgado Cristina
Université Clermont Auvergne, Centre Hospitalier Universitaire (CHU) Clermont-Ferrand, Institut National de la Santé et de la Recherche Médicale (INSERM), Neuro-Dol, Clermont-Ferrand, France.
Headache. 2025 Jul 25. doi: 10.1111/head.15015.
OBJECTIVES/BACKGROUND: Our aim was to compare the temporal dynamics of light and cephalic mechanical sensitivities in male and female mice as they relate to migraine chronicization. Cutaneous and light hypersensitivities are among the most common features of migraine, with greater severity observed in females. In 3% of patients, episodic migraine progresses to a chronic form, and sensory hypersensitivity becomes persistent. The pathophysiology underlying this transformation is complex and not fully understood. Moreover, studies comparing the evolution of sensory hypersensitivity between sexes are scarce.
Systemic administration of isosorbide dinitrate (ISDN, 10 mg/kg) was used to induce migraine-like behaviors in C57BL/6 mice. Cephalic sensitivity was assessed using periorbital von Frey testing. Light sensitivity was evaluated using the elevated plus maze and light/dark box paradigms. The effectiveness of current migraine treatments, sumatriptan (1 mg/kg) and propranolol (20 mg/kg), was also evaluated.
A single ISDN injection induced transient cephalic mechanical hypersensitivity in both males and females, with no sex differences observed. Acute treatment with sumatriptan effectively blocked this hypersensitivity, showing similar efficacy in both sexes. Notably, light hypersensitivity was induced exclusively in acute ISDN-treated females, developing earlier, and persisting longer than cephalic mechanical hypersensitivity. Repeated ISDN administration resulted in persistent and dose-dependent sensory hypersensitivity in both sexes. Interestingly, the chronicization patterns were sex-specific; ISDN-treated females developed persistent light and cephalic mechanical hypersensitivities simultaneously, whereas ISDN-treated males showed delayed light aversion. Prophylactic treatment with propranolol prevented the chronicity of cephalic mechanical hypersensitivity in both sexes, and partially attenuated acute ISDN-induced mechanical and light hypersensitivities.
The progression from acute to chronic ISDN-induced cephalic mechanical and light hypersensitivities has sex-specific characteristics that mimic the clinical features of migraine. These findings support the involvement of distinct underlying mechanisms and highlight the need for tailored treatment strategies to optimize migraine management in both male and female populations.
目的/背景：我们的目的是比较雄性和雌性小鼠光敏感性和头部机械敏感性的时间动态变化，以及它们与偏头痛慢性化的关系。皮肤和光过敏是偏头痛最常见的特征之一，女性中更为严重。3%的患者中，发作性偏头痛会进展为慢性形式，感觉过敏会持续存在。这种转变背后的病理生理学很复杂，尚未完全了解。此外，比较两性之间感觉过敏演变的研究很少。
使用硝酸异山梨酯（ISDN，10mg/kg）全身给药诱导C57BL/6小鼠出现偏头痛样行为。使用眶周von Frey测试评估头部敏感性。使用高架十字迷宫和明暗箱范式评估光敏感性。还评估了当前偏头痛治疗药物舒马曲坦（1mg/kg）和普萘洛尔（20mg/kg）的疗效。
单次注射ISDN在雄性和雌性小鼠中均诱导出短暂的头部机械性超敏反应，未观察到性别差异。舒马曲坦急性治疗有效阻断了这种超敏反应，在两性中显示出相似的疗效。值得注意的是，光超敏反应仅在急性ISDN治疗的雌性小鼠中诱导出现，比头部机械性超敏反应出现更早且持续时间更长。重复注射ISDN导致两性中出现持续且剂量依赖性的感觉超敏反应。有趣的是，慢性化模式具有性别特异性；ISDN治疗的雌性小鼠同时出现持续的光和头部机械性超敏反应，而ISDN治疗的雄性小鼠则表现出延迟的光厌恶。普萘洛尔预防性治疗可防止两性中头部机械性超敏反应的慢性化，并部分减轻急性ISDN诱导的机械性和光超敏反应。
从急性到慢性ISDN诱导的头部机械性和光超敏反应的进展具有性别特异性特征，类似于偏头痛的临床特征。这些发现支持了不同潜在机制的参与，并强调需要定制治疗策略以优化男性和女性人群的偏头痛管理。
