n-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)tetrahydropyrazine-1(2h)-carboxamide and Dry-Eye-Syndromes

This study reports the findings of two classes of corneal afferents excited by drying of the cornea (dry responses) in isoflurane-anesthetized rats: cold-sensitive (CS; 87%) and cold-insensitive (CI; 13%) neurons. Compared with CI neurons, CS neurons showed significantly higher firing rates over warmer corneal temperatures (~31-15°C) and greater responses to menthol, drying, and wetting of the cornea but lower responses when hyperosmolar solutions were applied to the ocular surface. We proposed that the dry responses of these corneal afferents derive from cooling and an increased osmolarity of the ocular surface, leading to the production of basal tears. An ocular application of the transient receptor potential channel TRPM8 antagonist BCTC (20 μM) decreased the dry responses by ~45-80% but failed to completely block them, whereas the TRPA1 antagonist HC030031 did not influence the responses to drying of the cornea or hyperosmolar tears. Furthermore, the responses produced by cold stimulation of the cornea accounted for only 28% of the dry responses. These results support the view that the stimulus for basal tearing (corneal dryness) derives partly from cooling of the cornea that activates TRPM8 channels but that non-TRPM8 channels also contribute significantly to the dry responses and to basal tearing. Finally, we hypothesized that activation of TRPM8 by cooling in CS corneal afferents not only gives rise to the sensation of ocular coolness but also to the "wetness" perception (Thunberg's illusion), whereas a precise role of the CI afferents in basal tearing and other ocular dryness-related functions such as eye blink and the "dryness" sensation remain to be elucidated.

Topics: Acetanilides; Action Potentials; Analysis of Variance; Animals; Cornea; Disease Models, Animal; Dose-Response Relationship, Drug; Dry Eye Syndromes; Eye; Male; Mannitol; Neurons, Afferent; Osmolar Concentration; Purines; Pyrazines; Pyridines; Rats; Rats, Sprague-Dawley; Reaction Time; Stimulation, Chemical; Tears; Temperature; Transient Receptor Potential Channels; Vision, Ocular

Basal tearing is crucial to maintaining ocular surface wetness. Corneal cold thermoreceptors sense small oscillations in ambient temperature and change their discharge accordingly. Deletion of the cold-transducing ion channel Transient receptor potential cation channel subfamily M member 8 (TRPM8) in mice abrogates cold responsiveness and reduces basal tearing without affecting nociceptor-mediated irritative tearing. Warming of the cornea in humans also decreases tearing rate. These findings indicate that TRPM8-dependent impulse activity in corneal cold receptors contributes to regulating basal tear flow.

Topics: 4-Aminopyridine; Animals; Cold Temperature; Cornea; Dry Eye Syndromes; Menthol; Mice; Mice, Transgenic; Ocular Physiological Phenomena; Pyrazines; Pyridines; Shaker Superfamily of Potassium Channels; Tears; Thermoreceptors; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPM Cation Channels