Sex differences in photophobic behaviors following cortical spreading depression in rats

Purpose: Photophobia is a common and debilitating symptom associated with migraine. Women are disproportionately affected by migraines, with a higher prevalence and more severe symptoms compared to men. This study investigated the effects of cortical spreading depression on light-aversive and dark-seeking behaviors in a rat model, with an emphasis on sex differences. Method: Experiments were conducted on seven to eight-week-old male and female Sprague Dawley rats. cortical spreading depression was modeled by injections of potassium chloride or artificial cerebrospinal fluid into the occipital cortex through a guide cannula. Key behavioral assessments included light-aversive and dark-seeking behaviors measured using a three-chamber box, pupil to iris ratio, periorbital tightening, periorbital allodynia and facial withdrawal thresholds. Results: Our results demonstrated that cortical potassium chloride injections significantly increased photophobic behaviors, particularly in female rats. Specifically, potassium chloride-injected females demonstrated a significant reduction in the time spent in the light chamber (p = 0.001) and increased time in the dark chamber compared to control rats (p = 0.01), indicating heightened light-aversion. Females exhibited more substantial pupil constriction and eyelid closure at 180 min after potassium chloride injection compared to artificial cerebrospinal fluid injection, suggesting a stronger physiological response to light. Similarly, a greater percent of female rats displayed periorbital allodynia (withdrawal threshold <6 g) over a post injection time course compared to male rats. Among rats that exhibited periorbital allodynia at least two consecutive time points, females had significantly lower facial withdrawal thresholds than males at 60-, 90-, 120-, and 180-min post injection (p < 0.05), suggesting a difference in magnitude and duration. Furthermore, the area under the curve for the time course experiment indicated development of tactile allodynia in periorbital region among female rats (p < 0.0001). Conclusion: Altogether these findings highlight the importance of considering sex-specific differences in developing therapeutic strategies for the treatment of migraine. We report for the first time a complete time course analysis of migraine-related responses, providing a comprehensive overview of the dynamics involved. The results suggest that potassium chloride-induced cortical spreading depression may offer a valuable model for studying the underlying mechanisms and sex differences of photophobia in migraine, aiding in the development of targeted treatments.