Abstract
Purpose :
NaV1.7 channel is genetically implicated in the transmission of corneal pain; however, pharmacological evidence supporting this role is currently lacking. We tested the hypothesis that selective pharmacological inhibition of NaV1.7 in the cornea would relieve ocular discomfort using rodent models of chronic and acute ocular pain.
Methods :
Experimental procedures were approved by IACUC in accordance with NIH Guide for Care and Use of Laboratory Animals and conducted at an AAALAC-accredited facility.
SD rats underwent surgery to remove lacrimal glands unilaterally. Animals that developed > 2-fold increase in the blink rate vs. contralateral eye at 2 weeks post-surgery were selected for the study (N=8). Compound E, a NaV1.7 selective inhibitor, was administered topically at 3 concentrations (1%, 2%, and 4%) to the affected eye once a day. Topical TTX (0.3%) was used a positive control. Number of blinks were counted for 5 minutes in both eyes at pre-drug, 5 min, 15 min, 30 min, 1 hour, 2 hours, and 4 hours post instillation. ANOVA test was used to determine statistical significance.
Naive CD-1 mice received topical ocular dosing of compounds C (3%), D (1.5%), and E(4%) followed by topical challenge with 0.1% formalin or 0.01% capsaicin. Topical proparacaine (0.5%) was used as a positive control. Number of irritant-induced blinks were counted for 20 seconds at baseline and after drug pretreatment. Student’s t-test was used to determine statistical significance.
Results :
Topical administration of compound E dose dependently relieved ocular discomfort in the rat dry eye model with ED50=0.9%. The effect lasted for over 4 hours. Compounds C, D, and E as well as proparacaine had no effect in the mouse model of acute pain.
Conclusions :
Our results are consistent with the hypothesis that selective inhibition of NaV1.7 in the cornea relieves chronic ocular pain caused by dryness of the ocular surface. However, selective inhibition of NaV1.7 in the cornea failed to relieve acute pain associated with topical irritants. We speculate that topical administration of capsaicin or formalin evoke responses that are not mediated by voltage-gated sodium channels in the cornea as the corneal nerve block with proparacaine also had no effect. Further investigations are needed to understand the mechanism of irritant-induced ocular discomfort.
This is a 2020 ARVO Annual Meeting abstract.