Modulation of corneal sensory processing and pain responses by dry eye and corneal wounding

Background Dry eye disease (DED) is a multifactorial disorder of the ocular surface in which tear film instability, epithelial barrier disruption, and neurosensory dysfunction contribute to symptom generation. Although several contributing factors have been identified, how different forms of ocular surface stress affect sensory pathways and behavioral responses remains unclear. Purpose This study aimed to evaluate corneal barrier function, sensory responses, and pain-related behaviors across acute and chronic dry eye and corneal injury models, and to assess stimulus-specific responses associated with TRPV1 and TRPM8 mediated pathways. Methods Female C57BL/6 J wild type and Mmp9KO mice were evaluated in acute desiccating stress (DS), chronic lacrimal gland excision (LGE) and aging, and corneal epithelial debridement models. Tear production, corneal barrier integrity, and mechanical and chemical sensitivity were assessed using established assays. Behavioral responses, including palpebral aperture height–width ratio (HWR), blink frequency, and pawing, were quantified following stimulation with capsaicin, hypertonic saline, and menthol. Human dry eye subjects were analyzed using video based measurements of HWR and blink frequency. Results Acute and chronic dry eye models and patients showed reduced palpebral aperture and decreased mechanical sensitivity. Sensitivity to CO₂ gas was unchanged, except in Mmp9KO. Capsaicin, hypertonic saline, and menthol reduced HWR in acute dry eye, with the greatest effect from capsaicin. Chronic dry eye showed reduced sensitivity to capsaicin and no change to hypertonic saline. Corneal debridement reduced mechanical sensitivity but increased responses to chemical stimulation. Conclusion Reduced mechanical corneal sensitivity and palpebral aperture HWR represent consistent sensory phenotypes across dry eye models and patients, supporting translational relevance. Divergent responses to chemical stimuli between acute and chronic dry eye suggest neurosensory processing evolves with disease chronicity and engages distinct sensory pathways.