Project Summary Ocular pain and photophobia are common and debilitating conditions associated with migraine and dry eye disease (DED). Persistent pain, dry eye, and/or photophobia are also experienced by nearly 40% of patients who have received refractive surgery. A common neuroanatomical substrate in migraine, DED, and refractive surgery is the trigeminal nerve, specifically the ophthalmic branch, which is involved in reflex homeostatic regulation of the cornea and dura. It is well known that damage to these reflex circuits leads to overt sensations of pain, yet the underlying mechanisms are poorly understood and effective non-opioid treatments are lacking. We hypothesize that the trigeminal neurons projecting to the cornea and dura are modulated by feedback from light-sensing cells in the eye, as well as by interaction with infiltrating immune cells leading to dysregulation of the reflex pathways and amplification of sensory responses – causing hypersensitivities to touch and light (photophobia). We will test this hypothesis in rodent models of migraine, DED, and refractive surgery by identifying molecular mechanisms and neural pathways common to the three pain models, using neuroanatomical, physiological, and behavioral approaches. Experiments will include investigation of potential therapeutic targets, including CGRP, TRPM3, and melanopsin, all of which have been previously implicated in photophobia. These studies will elucidate key cellular and molecular changes underlying the development of ocular pain and photophobia in migraine, DED, and refractive surgery, and will guide therapeutic development.