Sex influences the progression of cephalic mechanical and light hypersensitivities in a mouse model of chronic migraine.

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.

Methods: 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.

Results: 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.

Conclusion: 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.