title: Hyperosmolar tears enhance cooling sensitivity of the corneal nerves in rats: possible neural basis for cold-induced dry eye pain.
abstract: OBJECTIVE
  Tear hyperosmolarity is a ubiquitous feature of dry-eye disease. Although dry-eye patients' sensitivity to cooling is well known, the effects of tear hyperosmolarity on a small amount of cooling in the corneal nerves have not been quantitatively examined. Recently reported corneal afferents, high-threshold cold sensitive plus dry-sensitive (HT-CS + DS) neurons, in rats is normally excited by strong (>4°C) cooling of the cornea, which, when applied to healthy humans, evokes the sensation of discomfort. However, corneal cooling measured between blinks does not exceed 2°C normally. Thus, we sought to determine if these nociceptors could be sensitized by hyperosmolar tears such that they are now activated by small cooling of the ocular surface.
  
  
  METHODS
  Trigeminal ganglion neurons innervating the cornea were extracellularly recorded in isoflurane-anesthetized rats. The responses of single corneal neurons to cooling stimuli presented in the presence of hyperosmolar (350-800 mOsm NaCl) tears were examined.
  
  
  RESULTS
  The HT-CS + DS neurons with thresholds averaging 4°C cooling responded to cooling stimuli presented after 15 minutes of hyperosmolar tears with thresholds of less than 1°C. The response magnitudes also were enhanced so that the responses to small (2°C) cooling emerged, where none was observed before.
  
  
  CONCLUSIONS
  These results demonstrate that after exposure to hyperosmolar tears, these nociceptive corneal neurons now begin to respond to the slight cooling normally encountered between blinks, enabling the painful information to be carried to the brain, which could explain the cooling-evoked discomfort in dry eye patients.
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, United States Department of Ophthalmology, Weill Cornell Medical College, New York, New York, United States.
authors.forename: Harumitsu
authors.initials: H
authors.lastname: Hirata
authors.affiliation: Department of Ophthalmology, Weill Cornell Medical College, New York, New York, United States.
authors.forename: Mark I
authors.initials: MI
authors.lastname: Rosenblatt
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D003080:Cold Temperature; D003315:Cornea / Q000294:innervation*; D004195:Disease Models, Animal; D015352:Dry Eye Syndromes / Q000503:physiopathology*; D005074:Evoked Potentials, Visual / Q000502:physiology; D058447:Eye Pain / Q000503:physiopathology*; D008297:Male; D009475:Neurons, Afferent / Q000502:physiology*; D009994:Osmolar Concentration; D051381:Rats; D017207:Rats, Sprague-Dawley; D012684:Sensory Thresholds / Q000502:physiology; D013666:Tears / Q000737:chemistry*; D012668:Trigeminal Ganglion / Q000502:physiology*
keywords: corneal nerves; dry eye discomfort; dry eye disease; rats; trigeminal ganglion