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Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea

Nature Medicine volume 16, pages 1396–1399 (2010)Cite this article

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Abstract

Basal tearing is crucial to maintaining ocular surface wetness. Corneal cold thermoreceptors sense small oscillations in ambient temperature and change their discharge accordingly. Deletion of the cold-transducing ion channel Transient receptor potential cation channel subfamily M member 8 (TRPM8) in mice abrogates cold responsiveness and reduces basal tearing without affecting nociceptor-mediated irritative tearing. Warming of the cornea in humans also decreases tearing rate. These findings indicate that TRPM8-dependent impulse activity in corneal cold receptors contributes to regulating basal tear flow.

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Figure 1: Response characteristics and morphology of cold-sensitive terminals of the mouse cornea.
Figure 2: Response of corneal terminals to cooling ramps and dependence of tear secretion rate on corneal temperature.

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Acknowledgements

We thank E. Quintero, A. Miralles, M. Bayonas, A. Estirado, S. Ingham and A. Pérez-Vegara for skillful technical assistance and P. Orio for help with the spike frequency analysis. The Trpa1−/− mice were a generous gift from D. Corey (Harvard Medical School). This work was supported by the Spanish MICINN: projects BFU2008-04425 to C.B., BFU2007-61855 to F.V., SAF2008-00529 to J.G., SAF2008-01004 to D.E. and CONSOLIDER-INGENIO 2010 CSD2007-00023, and by the Fundación de Investigación Oftalmológica, Instituto de Oftalmología Fernandez-Vega and Fundación M.C.- Masadeu-Peterson. R.M. thanks the support of FONDECYT-1100983.

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Authors and Affiliations

  1. Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, San Juan de Alicante, Spain

    Andrés Parra, Rodolfo Madrid, Diego Echevarria, Cruz Morenilla-Palao, M Carmen Acosta, Juana Gallar, Félix Viana & Carlos Belmonte

  2. Departamento de Biología, Facultad de Química y Biología, Universidad de Santiago de Chile, Santiago, Chile

    Rodolfo Madrid

  3. Fundación de Investigación Oftalmológica, Instituto de Oftalmología Fernandez-Vega, Oviedo, Spain

    Susana del Olmo & Carlos Belmonte

  4. Department of Biological Structure, University of Washington, Seattle, Washington, USA

    Ajay Dhaka

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  1. Andrés Parra
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Contributions

A.P. performed the electrophysiological experiments and their analysis and contributed to behavioral experiments in mice. R.M. contributed to the planning and development of the electrophysiological recordings and to the analysis of data and preparation of figures. D.E. and S.d.O. performed the histological work and figures. C.M.-P. generated the Trpm8-EYFP mice and carried out preliminary morphological work. M.A. and J.G. performed and analyzed the behavioral experiments in mice and humans. A.D. provided the Trpm8−/− mice. F.V. participated in the planning of the work and preparation of the manuscript. C.B. planned and directed the study, performed some of the experiments and wrote the paper.

Corresponding author

Correspondence to Carlos Belmonte.

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Competing interests

C.B., J.G. and F.V. have submitted a patent application with application number P201031341 (Pharmaceutical composition including TRPM8 ligands to treat dry eye), Spain.

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Supplementary Methods, Supplementary Figures 1–5, Supplementary Table 1 and Supplementary Results (PDF 8958 kb)

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Parra, A., Madrid, R., Echevarria, D. et al. Ocular surface wetness is regulated by TRPM8-dependent cold thermoreceptors of the cornea. Nat Med 16, 1396–1399 (2010). https://doi.org/10.1038/nm.2264

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