Tear fluid hyperosmolality increases nerve impulse activity of cold thermoreceptor endings of the cornea

Pain. 2014 Aug;155(8):1481-1491. doi: 10.1016/j.pain.2014.04.025. Epub 2014 Apr 28.


Dry eye disease (DED) is a multifactorial disorder affecting the composition and volume of tears. DED causes ocular surface dryness, cooling, and hyperosmolality, leading ultimately to corneal epithelium damage and reduced visual performance. Ocular discomfort is the main clinical symptom in DED. However, the peripheral neural source of such unpleasant sensations is still unclear. We analyzed in excised, superfused mouse eyes, the effect of NaCl-induced hyperosmolality (325-1005 mOsm·kg(-1)) on corneal cold thermoreceptor and polymodal nociceptor nerve terminal impulse (NTI) activity. Osmolality elevations at basal corneal temperature (33.6°C) linearly increased the ongoing NTI frequency of cold thermoreceptors, at a mean rate of 0.34 imp·s(-1)/10 mOsm. This frequency increase became significant with osmolality values greater than 340 mOsm. Comparison of cold thermoreceptor activity increase induced by a dynamic temperature reduction of 1.8°C under iso- and hyperosmolal (360-mOsm) conditions provided evidence that more than 50% of the increased firing response was attributable to hyperosmolality. Comparatively, activation of corneal polymodal nociceptor endings by hyperosmolal solutions started with values of 600 mOsm and greater. Sensitization of polymodal nociceptors by continuous perfusion with an "inflammatory soup" (bradykinin, histamine, prostaglandin E2 [PGE2], serotonin, and adenosine triphosphate [ATP]) did not enhance their activation by hyperosmolal solutions. High osmolality also altered the firing pattern and shape of cold and polymodal NTIs, possibly reflecting disturbances in local membrane currents. Results strongly suggest that tear osmolality elevations in the range observed in DED predominantly excite cold thermoreceptors, supporting the hypothesis that dryness sensations experienced by these patients are due, at least in part, to an augmented activity of corneal cold thermoreceptors.

Keywords: Cold thermoreceptors; Cornea; Dry eye; Hyperosmotic stress; Polymodal nociceptors; Tear osmolality.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / physiology*
  • Animals
  • Cold Temperature
  • Cornea / innervation
  • Cornea / physiopathology*
  • Dry Eye Syndromes / physiopathology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred ICR
  • Nerve Endings / physiology
  • Osmolar Concentration
  • Tears / physiology*
  • Thermoreceptors / physiology*