title: Abnormal activity of corneal cold thermoreceptors underlies the unpleasant sensations in dry eye disease.
abstract: Dry eye disease (DED) affects >10% of the population worldwide, and it provokes an unpleasant sensation of ocular dryness, whose underlying neural mechanisms remain unknown. Removal of the main lachrymal gland in guinea pigs caused long-term reduction of basal tearing accompanied by changes in the architecture and density of subbasal corneal nerves and epithelial terminals. After 4 weeks, ongoing impulse activity and responses to cooling of corneal cold thermoreceptor endings were enhanced. Menthol (200 μM) first excited and then inactivated this augmented spontaneous and cold-evoked activity. Comparatively, corneal polymodal nociceptors of tear-deficient eyes remained silent and exhibited only a mild sensitization to acidic stimulation, whereas mechanonociceptors were not affected. Dryness-induced changes in peripheral cold thermoreceptor responsiveness developed in parallel with a progressive excitability enhancement of corneal cold trigeminal ganglion neurons, primarily due to an increase of sodium currents and a decrease of potassium currents. In corneal polymodal nociceptor neurons, sodium currents were enhanced whereas potassium currents remain unaltered. In healthy humans, exposure of the eye surface to menthol vapors or to cold air currents evoked unpleasant sensations accompanied by increased blinking frequency that we attributed to cold thermoreceptor stimulation. Notably, stimulation with menthol reduced the ongoing background discomfort of patients with DED, conceivably due to use-dependent inactivation of cold thermoreceptors. Together, these data indicate that cold thermoreceptors contribute importantly to the detection and signaling of ocular surface wetness, and develop under chronic eye dryness conditions an injury-evoked neuropathic firing that seems to underlie the unpleasant sensations experienced by patients with DED.
authors.affiliation: Instituto de Neurociencias, Universidad Miguel Hernández-CSIC, San Juan de Alicante, Spain Department of Ophthalmology, Semmelweis University, Budapest, Hungary Laboratory of Neurophysiology, Department of Biomedicine, School of Medicine, University of Barcelona, Barcelona, Spain Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain Instituto Universitario Fernández-Vega, Universidad de Oviedo and Fundación de Investigación Oftalmológica, Oviedo, Spain Departamento de Fisiología, Genética y Microbiología, Universidad de Alicante, San Vicente del Raspeig, Spain.
authors.forename: Illés
authors.initials: I
authors.lastname: Kovács
authors.forename: Carolina
authors.initials: C
authors.lastname: Luna
authors.forename: Susana
authors.initials: S
authors.lastname: Quirce
authors.forename: Kamila
authors.initials: K
authors.lastname: Mizerska
authors.forename: Gerard
authors.initials: G
authors.lastname: Callejo
authors.forename: Ana
authors.initials: A
authors.lastname: Riestra
authors.forename: Laura
authors.initials: L
authors.lastname: Fernández-Sánchez
authors.forename: Victor M
authors.initials: VM
authors.lastname: Meseguer
authors.forename: Nicolás
authors.initials: N
authors.lastname: Cuenca
authors.forename: Jesús
authors.initials: J
authors.lastname: Merayo-Lloves
authors.forename: M Carmen
authors.initials: MC
authors.lastname: Acosta
authors.forename: Xavier
authors.initials: X
authors.lastname: Gasull
authors.forename: Carlos
authors.initials: C
authors.lastname: Belmonte
authors.forename: Juana
authors.initials: J
authors.lastname: Gallar
mesh_terms: D000200:Action Potentials / Q000502:physiology; D000328:Adult; D000818:Animals; D001767:Blinking / Q000502:physiology; D003080:Cold Temperature; D003315:Cornea / Q000294:innervation / Q000503:physiopathology*; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000473:pathology* / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009475:Neurons, Afferent / Q000502:physiology; D009619:Nociceptors / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D012677:Sensation; D011984:Sensory Receptor Cells / Q000378:metabolism; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013552:Swine; D013666:Tears; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013823:Thermoreceptors / Q000502:physiology*; D012668:Trigeminal Ganglion / Q000473:pathology; D055815:Young Adult
chemical_list: D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers; D013779:Tetrodotoxin; D019789:Tetraethylammonium