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

Abstract

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.

Functional Properties of Sensory Nerve Terminals of the Mouse Cornea

“…Also, when this high-osmolality solution was applied, the NTI irregular firing pattern changed to a bursting pattern and the shape of NTIs was altered, becoming wider and of smaller amplitude (data not shown; see also Ref. 35). The TRPA1 agonist AITC (100 lM) was tested in 9 terminals and weakly activated 4 of them, while the TRPV1 agonist capsaicin (1 lM) …”

“…17,35 The posterior pole of the eyeball and optic nerve was introduced into a silicone tube located at the bottom of a recording chamber filled with saline and secured in place by continuous suction. The eye was continuously superfused with a physiological saline solution of the following composition (in mM): NaCl (128), KCl (5), NaH 2 PO 4 (1), NaHCO 3 (26), CaCl 2 (2.4), MgCl 2 (1.3), and glucose (10).…”

“…A variable sensitivity of canonical cold thermoreceptors to these stimuli has been reported earlier. [17][18][19]24,29,30,32,35,55 This is not exceptional. Other classes of peripheral somatosensory receptors equipped with specific transducing channels that confer preferential sensitivity for a particular form of stimulating energy, also express transduction channels for other stimulus qualities.…”

“…Under normal environmental conditions, it has been postulated that small changes in ocular surface temperature and osmolality resulting from tear fluid evaporation at the exposed eye surface are encoded by HB-LT cold thermoreceptors 17,23,24,28,29,35,58,59 and transmitted to second-order Vi/Vc neurons. 20,78 When there is excessive evaporation and/or hyperosmolarity of tear film, the LB-HT cold thermoreceptors may also be recruited, and evoke a sense of irritation through the same pain-labeled pathways as corneal mechano-and polymodal nociceptor nerve fibers.…”

Neuropathic ocular pain: an important yet underevaluated feature of dry eye

“…The above inflammatory environment, along with other stresses such as hyperosmolarity, 61 can affect the function of nociceptors with alterations in ion channel activity (increased sodium and calcium currents at the nociceptor terminal) through changes in gene expression and transcription, as reviewed by Pergolizzi et al 28 and Costigan et al 62 The resultant phenotypic change of reduced activation thresholds and increased excitability is termed peripheral sensitization ( Figure 3). Peripheral sensitization can be reversed after resolution of the inciting stress and normalization of ocular surface inflammation ( Figure 2).…”