Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Brief Communication
  • Published:

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


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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others


  1. Moss, S.E., Klein, R. & Klein, B.E. Optom. Vis. Sci. 85, 668–674 (2008).

    Article  Google Scholar 

  2. Tsubota, K. Prog. Retin. Eye Res. 17, 565–596 (1998).

    Article  CAS  Google Scholar 

  3. Lehrer, S., Bogursky, E., Yemini, M., Kase, N.G. & Birkenfeld, A. Am. J. Obstet. Gynecol. 170, 835–837 (1994).

    Article  CAS  Google Scholar 

  4. Dartt, D.A. Prog. Retin. Eye Res. 28, 155–177 (2009).

    Article  Google Scholar 

  5. Purslow, C. & Wolffsohn, J. Optom. Vis. Sci. 84, 197–201 (2007).

    Article  Google Scholar 

  6. Brock, J.A., McLachlan, E.M. & Belmonte, C. J. Physiol. (Lond.) 512, 211–217 (1998).

    Article  CAS  Google Scholar 

  7. McKemy, D.D., Neuhausser, W.M. & Julius, D. Nature 416, 52–58 (2002).

    Article  CAS  Google Scholar 

  8. Madrid, R. et al. J. Neurosci. 26, 12512–12525 (2006).

    Article  CAS  Google Scholar 

  9. Kwan, K.Y. et al. Neuron 50, 277–289 (2006).

    Article  CAS  Google Scholar 

  10. Bandell, M. et al. Neuron 41, 849–857 (2004).

    Article  CAS  Google Scholar 

  11. Viana, F., de la Pena, E. & Belmonte, C. Nat. Neurosci. 5, 254–260 (2002).

    Article  CAS  Google Scholar 

  12. Madrid, R. J. Neurosci. 29, 3120–3131 (2009).

    Article  CAS  Google Scholar 

  13. Dhaka, A. et al. Neuron 54, 371–378 (2007).

    Article  CAS  Google Scholar 

  14. Colburn, R.W. et al. Neuron 54, 379–386 (2007).

    Article  CAS  Google Scholar 

  15. Belmonte, C., Brock, J.A. & Viana, F. Exp. Brain Res. 196, 13–30 (2009).

    Article  Google Scholar 

  16. Acosta, M.C. et al. Invest. Ophthalmol. Vis. Sci. 45, 2333–2336 (2004).

    Article  Google Scholar 

  17. Niederer, R.L., Perumal, D., Sherwin, T. & McGhee, C.N. Br. J. Ophthalmol. 91, 1165–1169 (2007).

    Article  CAS  Google Scholar 

  18. Wolkoff, P., Nojgaard, J.K., Troiano, P. & Piccoli, B. Occup. Environ. Med. 62, 4–12 (2005).

    Article  CAS  Google Scholar 

  19. Belmonte, C. J. Refract. Surg. 23, 598–602 (2007).

    Article  Google Scholar 

  20. Acosta, M.C., Belmonte, C. & Gallar, J. J. Physiol. (Lond.) 534, 511–525 (2001).

    Article  CAS  Google Scholar 

Download references


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.

Author information

Authors and Affiliations



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.

Ethics declarations

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.

Supplementary information

Supplementary Text and Figures

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

Rights and permissions

Reprints and permissions

About this article

Cite this article

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).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing