Dynamic Sensitivity of Corneal TRPM8 Receptors to Menthol Instillation in Dry Eye Versus Normal Subjects

Purpose: To assess the sensitivity of corneal cold receptors to a known transient receptor potential melastatin 8 (TRPM8) agonist, menthol, in dry eye and normals, and to determine whether factors such as disease duration or age affect responses. Methods: Dry eye disease (DED) (N=33) and normal (N=15) subjects were randomly assigned to receive Rohto((R)) Hydra (0.01% menthol) or Systane((R)) Ultra treatments (OU) in a prospective, double-blind, crossover study. DED subjects had documented disease and symptom response scores >2 on a 0- to 5-point scale. Normals had no history of DED and scores <2 on the same scale. Endpoints included mean cooling score (0=not cool and 10=very cool) evaluated at 0, 0.5, 1, 2, 3, and 4min post-instillation, sum cooling scores (5 time points, range 0-60), and ocular signs and symptoms. Results: Mean (SD) ages were similar, 62.2 +/- 8.6-year (DED) versus 53.5 +/- 7.6-year (normal). Corneal sensitivity scores were not different between groups. Mean cooling scores at 0.5-4min post-menthol instillation were significantly higher in DED subjects (P0.03). Sum cooling scores were significantly higher (P=0.04) in DED subjects with a disease duration <10 years (N=18, 28.3 +/- 2.58) versus 10 years (N=15, 20.2 +/- 2.76). Age did not affect cooling response in either group. Conclusion: DED subjects had greater sensitivity to cold than normal subjects. DED duration, and not age, was critical to cooling sensitivity. The finding that cooling scores were higher in subjects with DED for less than 10 years compared to more than 10 years suggests that corneal cold receptor sensitivity decreases as the duration of DED increases.