Resveratrol increases tear production and spontaneous ocular pain after corneal abrasion in male, but not female, rats using a preclinical model of photorefractive keratectomy (PRK)

Photorefractive keratectomy (PRK) is an alternative to LASIK and can cause intense acute pain that is often not relieved by standard treatments. To assess potential therapeutics for this type of acute pain, appropriate preclinical models are needed. Herein we describe a rodent preclinical model of PRK and a multi-faceted approach to determine the therapeutic potential of resveratrol, a natural phytoestrogen, on pain, tear production, and the corneal epithelium. Studies were conducted in male and female Sprague-Dawley rats. Heptanol was applied to one eye and the superficial corneal epithelium was removed, mimicking the abrasion seen in PRK. Spontaneous pain was assessed with orbital tightening (OT) scores for 7 days. Corneal abrasion increased OT scores in both male and female rats with peak responses at 24 - 48 hours. Topical application of resveratrol had a sex-specific effect on OT scores and tear production. Resveratrol increased OT scores in abraded males, but not females, at 72 hours and 1 week after abrasion. Resveratrol dose-dependently increased tear production in abraded males, but had no effect in abraded females. While there was no correlation between OT score at 1 week and tear production, CGRP content of corneal nerves was positively correlated with 1 week OT score. There was also a significant increase in CD68-labeled macrophages in resveratrol-treated abraded corneas as compared to naive corneas. These findings demonstrate the usefulness of our preclinical PRK model for the assessment of ocular pain therapeutics and indicate that topical resveratrol may not be useful for managing PRK-induced pain. ### Competing Interest Statement Gregory Dussor and Theodore J. Price and Dennis I. Robbins are co-founders of Teds Brain Science a company developing resveratrol-based therapeutics for pain. All other authors report no conflicts of interest.