Mice with Desiccating Stress-Induced Dry Eye Develop Trigeminal Neuralgia, Despite Decreased Corneal Sensitivity and Nerve Fiber Degeneration

Abstract

Purpose: Pain is a major symptom of patients suffering from chronic Dry Eye disease. To begin to understand if the immunopathogenesis of desiccating stress (DS)-induced Dry Eye is associated with a pain response, corneal sensitivity, corneal nerve fiber density, neuropeptides and trigeminal neuralgia were evaluated over the course of disease.

Methods: Dry Eye disease was induced by exposing female C57BL/6 mice to desiccating stress (DS: subcutaneous scopolamine (1.0mg/0.2ml) TID; humidity <40%; sustained airflow). At various time points mice were evaluated for corneal sensitivity using von Frey filaments (Dixon up-down method), corneal nerve fibers with immunohistochemistry, neuropeptides using ELISA and trigeminal neuralgia with behavorial testing.

Results: IHC on flat mount whole corneas revealed a significant decrease (p<0.01) corneal nerve fiber density at Day 10, 15 and 20 of DS using neuronal class III beta-tubulin (Tuj1+) staining. Mice with Dry Eye disease also developed decreased corneal sensitivity very early, at Day 1 (0.21±0.10 gram force) and Day 3 (0.41±0.14 gram force; p=0.05) of DS compared to baseline (0.04±0.006 gram force). Mice with Dry Eye disease also developed robust trigeminal neuralgia by Day 15 (pain behavorial score = 4.67±.39 out of a maximum of 6.0; p<0.001), which was associated with upregulation of neuropeptides in the trigeminal ganglia; calcitonin gene related peptide (CGRP) and substance P were significantly (p=0.05) upregulated in the trigeminal ganglia by Day 15 of DS.

Conclusions: These data suggest that DS mice develop trigeminal neuralgia, despite decreased corneal sensitivity and nerve fiber degeneration during the progression of experimental Dry Eye disease.

Keywords: 486 cornea: tears/tear film/dry eye • 557 inflammation • 565 innervation: sensation