TRPV1-expressing neurons are dispensable for photophobia: evidence from a novel mouse light sensitivity assay

Background: Light hypersensitivity, or photophobia, affects nearly 80% of people with migraine and is the most prevalent symptom after headache. Despite its high prevalence, the neural pathways underlying migraine-associated light hypersensitivity remain poorly understood, in part due to the lack of behavioral assays that directly assess light sensitivity in mice. Consequently, whether nociceptors contribute to the development of photophobia remains unclear. Methods: We established a novel light sensitivity assay (LSA) to quantify the response to light in mice by measuring facial grimacing. The assay was applied to evaluate light hypersensitivity elicited by three established migraine triggers: calcitonin gene-related peptide (CGRP), nitric oxide donor (sodium nitroprusside), and repeated stress. To determine the contribution of TRPV1 nociceptors, mice were treated with resiniferatoxin (RTX) to ablate these neurons. Results: The LSA detected light hypersensitivity following administration of CGRP, sodium nitroprusside, and repeated stress in wild-type (WT) mice. Sex differences were not observed in CGRP- or stress-induced light hypersensitivity. Furthermore, ablation of TRPV1 nociceptors did not reduce light hypersensitivity induced by migraine triggers. Conclusions: These findings present the LSA as a robust, reproducible, and easy to implement behavioral assay for measuring light sensitivity in preclinical migraine models. Our results further demonstrate that TRPV1 nociceptors are dispensable for the development of migraine-associated light hypersensitivity. This assay provides a useful method for investigating the mechanisms underlying light sensitivity and for evaluating potential therapeutic strategies.