Millions worldwide suffer from the ocular pain and diminished tearing of dry eye disease. Although great advances have been made in many aspects of dry eye research, one area of studies that of corneal nerves has lagged behind. Tear hyperosmolarity is ubiquitously present in dry eye disease and dysfunction of the corneal nerve contributes significantly to the initiation and/or perpetuation of dry eye disease. However, these two subjects have never been studied together. Thus, the proposed research will investigate the effect of tear hyperosmolarity on the corneal nerves responsible for tearing and pain sensation. We recently discovered in rats that special types of corneal nerves displayed many of the response characteristics that are consistent with these nerves serving the functions of tearing and pain sensation. We also discovered that these corneal nerves altered their sensitivities when the eyes were treated with the amounts of hyperosmolar tears found in dry eye patients. Thus, after the corneal nerves were treated with hyperosmolar tears, the nerves began to be excited by a gentle cooling (~1oC) of the cornea, indicating that the normally non-painful stimulus (mild cooling) now activated these neurons presumably giving rise to ocular pain. On the other hand, after the treatment with hyperosmolar tears these neurons began to be less excited by the stimulus thought to be critical for tearing (i.e., drying of the cornea). Therefore, the effects of tear hyperosmolarity on these nerves could explain the exaggerated eye pain and the diminished tearing that DE patients report. We propose to study the following questions in more detail: 1) what is the minimum amount of tear hyperosmolarity necessary to change the neural sensitivity;2) how long does the tear hyperosmolarity have to remain on the cornea for the nerves to change sensitivity, and does the longer tear hyperosmolarity necessarily lead to more or less activation of these neurons (i.e., more pain and fewer tears?);3) does the hyperosmolar tear-induced change become permanent, and if so, when? We have also discovered that these neurons show abnormal activity under extended hyperosmolar tear conditions (2 days). What are the mechanisms responsible for these sudden changes in activity? The answers to these questions could identify hyperosmolar tears as being a crucial determinant of the ocular pain and diminished tears found in DE patients. A variety of drugs such as antagonists for inflammatory mediators and membrane ion channels in corneal nerves and epithelia will be tested to block these sensitivity changes and the abnormal activities seen in these nerves. These pharmacological determinations of the changes in corneal nerve functions may lead to better understanding of the pathogenesis of dry eye diseases and offer new avenues of treatment for one of the most common and yet challenging diseases in our society.

Public Health Relevance

Millions of Americans suffer from dry eye disease. Hyperosmolar (concentrated) tears are constant presence in DE patients. We propose to determine if hyperosmolar tears will affect the corneal nerve functions so as to explain some of the signs and symptoms of dry eye disease, ocular pain and diminished tearing.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Special Emphasis Panel (DPVS)
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Mckie, George Ann
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Thomas Jefferson University
Schools of Medicine
United States
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Hirata, Harumitsu; Dallacasagrande, Valentina; Mizerska, Kamila et al. (2018) Ambient Air Currents Activate Corneal Nerves During Ocular Desiccation in Rats: Simultaneous Recordings of Neural Activity and Corneal Temperature. Invest Ophthalmol Vis Sci 59:4031-4043
Hirata, Harumitsu; Mizerska, Kamila; Dallacasagrande, Valentina et al. (2017) Estimating the Osmolarities of Tears During Evaporation Through the ""Eyes"" of the Corneal Nerves. Invest Ophthalmol Vis Sci 58:168-178
Hirata, Harumitsu; Mizerska, Kamila; Dallacasagrande, Valentina et al. (2017) Acute corneal epithelial debridement unmasks the corneal stromal nerve responses to ocular stimulation in rats: implications for abnormal sensations of the eye. J Neurophysiol 117:1935-1947
Hirata, Harumitsu; Mizerska, Kamila; Marfurt, Carl F et al. (2015) Hyperosmolar Tears Induce Functional and Structural Alterations of Corneal Nerves: Electrophysiological and Anatomical Evidence Toward Neurotoxicity. Invest Ophthalmol Vis Sci 56:8125-40
Hirata, Harumitsu; Rosenblatt, Mark I (2014) Hyperosmolar tears enhance cooling sensitivity of the corneal nerves in rats: possible neural basis for cold-induced dry eye pain. Invest Ophthalmol Vis Sci 55:5821-33