Sensory nerve fibres can detect changes in temperature over a remarkably wide range, a process that has been proposed to involve direct activation of thermosensitive excitatory transient receptor potential (TRP) ion channels1,2,3,4. One such channel—TRP melastatin 8 (TRPM8) or cold and menthol receptor 1 (CMR1)—is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below ∼26 °C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons5,6. However, some studies have questioned the contribution of TRPM8 to cold detection or proposed that other excitatory or inhibitory channels are more critical to this sensory modality in vivo7,8,9,10. Here we show that cultured sensory neurons and intact sensory nerve fibres from TRPM8-deficient mice exhibit profoundly diminished responses to cold. These animals also show clear behavioural deficits in their ability to discriminate between cold and warm surfaces, or to respond to evaporative cooling. At the same time, TRPM8 mutant mice are not completely insensitive to cold as they avoid contact with surfaces below 10 °C, albeit with reduced efficiency. Thus, our findings demonstrate an essential and predominant role for TRPM8 in thermosensation over a wide range of cold temperatures, validating the hypothesis2 that TRP channels are the principal sensors of thermal stimuli in the peripheral nervous system.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Jordt, S. E., McKemy, D. D. & Julius, D. Lessons from peppers and peppermint: the molecular logic of thermosensation. Curr. Opin. Neurobiol. 13, 487–492 (2003)
Caterina, M. J., Rosen, T. A., Tominaga, M., Brake, A. J. & Julius, D. A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398, 436–441 (1999)
Dhaka, A., Viswanath, V. & Patapoutian, A. Trp ion channels and temperature sensation. Annu. Rev. Neurosci. 29, 135–161 (2006)
Lumpkin, E. A. & Caterina, M. J. Mechanisms of sensory transduction in the skin. Nature 445, 858–865 (2007)
McKemy, D. D., Neuhausser, W. M. & Julius, D. Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58 (2002)
Peier, A. M. et al. A TRP channel that senses cold stimuli and menthol. Cell 108, 705–715 (2002)
Viana, F., de la Pena, E. & Belmonte, C. Specificity of cold thermotransduction is determined by differential ionic channel expression. Nature Neurosci. 5, 254–260 (2002)
Madrid, R. et al. Contribution of TRPM8 channels to cold transduction in primary sensory neurons and peripheral nerve terminals. J. Neurosci. 26, 12512–12525 (2006)
Reid, G. & Flonta, M. Cold transduction by inhibition of a background potassium conductance in rat primary sensory neurones. Neurosci. Lett. 297, 171–174 (2001)
McKemy, D. D. How cold is it? TRPM8 and TRPA1 in the molecular logic of cold sensation. Mol. Pain 1, 16–22 (2005)
Bautista, D. M. et al. TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124, 1269–1282 (2006)
Bandell, M. et al. Noxious cold ion channel TRPA1 is activated by pungent compounds and bradykinin. Neuron 41, 849–857 (2004)
Jordt, S. E. et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427, 260–265 (2004)
Story, G. M. et al. ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829 (2003)
Reid, G. ThermoTRP channels and cold sensing: what are they really up to? Pflugers Arch. 451, 250–263 (2005)
Stucky, C. L. et al. Overexpression of nerve growth factor in skin selectively affects the survival and functional properties of nociceptors. J. Neurosci. 19, 8509–8516 (1999)
Koltzenburg, M., Stucky, C. L. & Lewin, G. R. Receptive properties of mouse sensory neurons innervating hairy skin. J. Neurophysiol. 78, 1841–1850 (1997)
Iggo, A. Cutaneous thermoreceptors in primates and sub-primates. J. Physiol. Lond. 200, 403–430 (1969)
Schafer, K., Braun, H. A. & Kurten, L. Analysis of cold and warm receptor activity in vampire bats and mice. Pflugers Arch. 412, 188–194 (1988)
Rainville, P., Chen, C. C. & Bushnell, M. C. Psychophysical study of noxious and innocuous cold discrimination in monkey. Exp. Brain Res. 125, 28–34 (1999)
Reid, G. & Flonta, M. L. Cold current in thermoreceptive neurons. Nature 413, 480 (2001)
Maingret, F. et al. TREK-1 is a heat-activated background K(+) channel. EMBO J. 19, 2483–2491 (2000)
Askwith, C. C., Benson, C. J., Welsh, M. J. & Snyder, P. M. DEG/ENaC ion channels involved in sensory transduction are modulated by cold temperature. Proc. Natl Acad. Sci. USA 98, 6459–6463 (2001)
Pierau, F. K., Torrey, P. & Carpenter, D. O. Mammalian cold receptor afferents: role of an electrogenic sodium pump in sensory transduction. Brain Res. 73, 156–160 (1974)
Kreh, A., Anton, F., Gilly, H. & Handwerker, H. O. Vascular reactions correlated with pain due to cold. Exp. Neurol. 85, 533–546 (1984)
Fruhstorfer, H. & Lindblom, U. Vascular participation in deep cold pain. Pain 17, 235–241 (1983)
Hensel, H. & Zotterman, Y. The effect of menthol on the thermoreceptors. Acta Physiol. Scand. 24, 27–34 (1951)
Babes, A., Zorzon, D. & Reid, G. A novel type of cold-sensitive neuron in rat dorsal root ganglia with rapid adaptation to cooling stimuli. Eur. J. Neurosci. 24, 691–698 (2006)
Zurborg, S., Yurgionas, B., Jira, J. A., Caspani, O. & Heppenstall, P. A. Direct activation of the ion channel TRPA1 by Ca(2+). Nature Neurosci. 10, 277–279 (2007)
Doerner, J. F., Gisselmann, G., Hatt, H. & Wetzel, C. H. Transient receptor potential channel A1 is directly gated by calcium ions. J. Biol. Chem. (2007)
Bunting, M., Bernstein, K. E., Greer, J. M., Capecchi, M. R. & Thomas, K. R. Targeting genes for self-excision in the germ line. Genes Dev. 13, 1524–1528 (1999)
Hargreaves, K., Dubner, R., Brown, F., Flores, C. & Joris, J. A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32, 77–88 (1988)
We thank R. Nicoll for discussion and criticism, M. Tominaga for providing TRPM8 antiserum, T. Nikai for advice regarding behavioural assays, and J. Poblete for technical assistance throughout. This work was supported by grants from the NIH (D.J., A.I.B., S.-E.J. and C.L.S.), a Burroughs Welcome Fund Career Award in Biomedical Sciences (D.M.B.) and a postdoctoral fellowship from the International Human Frontier Science Program Organization (J.S.).
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
Supplementary Figure 1 shows RT-PCR analysis and in situ hybridization of TRPM8. The prevalence of neurons that normally would express TRPM8 in trigeminal ganglia has not changed in the TRPM8-/- littermates. Supplementary Figure 2 shows properties of C and AM fibers assessed using the skin-nerve preparation. Basal firing rates of sensory nerve fibers from TRPM8-deficient mice were substantially reduced compared to wild type controls. However all other electrical and mechanical properties of these fibers were unaltered by TRPM8 disruption. Supplementary Figure 3 shows mechanical and thermal (heat) thresholds for wild type and TRPM8-deficient littermates as determined by Von Frey filament and radiant heat behavioral paradigms, respectively. Similar responses were observed for both genotypes. Supplementary Figure 4 demonstrates that TRPA1-deficient mice have normal cold sensitivity, irrespective of whether male or female mice (not in estrus) were examined. Supplementary Table 1 shows that DRG and TG neurons from wild type or TRPM8-/- mice respond similarly to a variety of different chemical and thermal stimuli, irrespective of genotype. (PDF 482 kb)
This file contains Supplementary Video 1. This movie shows a representative two-plate choice test in which wild type or TRPM8-deficient mice are examined for exploratory behavior with surface temperatures adjusted to 30°C and 20°C, as shown. It is evident that the TRPM8-deficient mouse exhibits no preference for the warmer side during the 30 sec exploratory period, whereas the wild type littermate spends most of its time at 30°C. Moreover, the wild type mouse shows clear aversion to the colder side. (MOV 3376 kb)
About this article
Cite this article
Bautista, D., Siemens, J., Glazer, J. et al. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448, 204–208 (2007). https://doi.org/10.1038/nature05910
Neurobiology of Pain (2020)
Phylogenetics Identifies Two Eumetazoan TRPM Clades and an Eighth TRP Family, TRP Soromelastatin (TRPS)
Molecular Biology and Evolution (2020)
Transient receptor potential channels: current perspectives on evolution, structure, function and nomenclature
Proceedings of the Royal Society B: Biological Sciences (2020)
Proceedings of the National Academy of Sciences (2020)