Skip to content
Accessible Unlicensed Requires Authentication Published by De Gruyter October 18, 2016

Highway to thermosensation: a traced review, from the proteins to the brain

Ivan Ezquerra-Romano and Angel Ezquerra ORCID logo


Temperature maintenance and detection are essential for the survival and perpetuation of any species. This review is focused on thermosensation; thus a detailed and traced explanation of the anatomical and physiological characteristics of each component of this sensation is given. First, the proteins that react to temperature changes are identified; next, the nature of the neurons involved in thermosensation is described; and then, the pathways from the skin through the spinal cord to the brain are outlined. Finally, the areas of the brain and their interconnections where thermoperception arises are explained. Transduction of the external and internal temperature information is essentially mediated by the transient receptor potential ion channels (TRPs). These proteins are embedded in the neurons’ membrane and they hyper- or de-polarize neurons in function of the intrinsic voltage and the temperature changes. There are distinct TRP sensors for different temperature ranges. Interestingly, the primary afferent neurons have either cold or hot receptors, so they are dedicated separately to cold or hot sensation. The information is transmitted by different pathways from the skin to the brain, where it either remains separated or is integrated to generate a response. It seems that both the determination of how thermoperception is produced and how we interact with the world are dependent on the particular arrangement and nature of the components, the way of transduction of information and the communication between these elements.


We would like to thank Karishma Mahtini for her accurate comments and for proofreading the paper and to Mario Martinez Cepa for his altruistic and artistic drawings.


Adair, R.K. (1999). A model of the detection of warmth and cold by cutaneous sensors through effects on voltage-gated membrane channels. Proc. Nat. Acad. Sci. USA 96, 11825–11829.Search in Google Scholar

Andrew, D. and Craig, A. (2001). Spinothalamic lamina I neurones selectively responsive to cutaneous warming in cats. J. Physiol. 537, 489–495.Search in Google Scholar

Arrigoni, C., Rohaim, A., Shaya, D., Findeisen, F., Stein, R.A., Nurva, S.R.,... Minor, D.L. (2016). Unfolding of a temperature-sensitive domain controls voltage-gated channel activation. Cell 164, 922–936.Search in Google Scholar

Askwith, C.C., Benson, C.J., Welsh, M.J., and Snyder, P.M. (2001). DEG/ENaC ion channels involved in sensory transduction are modulated by cold temperature. Proc. Nat. Acad. Sci. USA 98, 6459–6463.Search in Google Scholar

Bagriantsev, S.N., Clark, K.A., and Minor, D.L., Jr. (2012). Metabolic and thermal stimuli control K(2P)2.1 (TREK-1) through modular sensory and gating domains. EMBO J. 31, 3297–3308.Search in Google Scholar

Bautista, D.M., Siemens, J., Glazer, J.M., Tsuruda, P.R., Basbaum, A.I., Stucky, C.L.,... Julius, D. (2007). The menthol receptor TRPM8 is the principal detector of environmental cold. Nature 448, 204–208.Search in Google Scholar

Bear, M.F., Connors, B.W., and Paradiso, M.A. (2007). Neuroscienze. esplorando il cervello. With CD-ROM Elsevier srl.Search in Google Scholar

Benham, C.D., Gunthorpe, M.J., and Davis, J.B. (2003). TRPV channels as temperature sensors. Cell Calcium 33, 479–487.Search in Google Scholar

Boulant, J. (1980). Hypothalamic control of thermoregulation: neurophysiological basis. Handbook of the Hypothalamus 3, 1–82.Search in Google Scholar

Boulant, J. (1998). Hypothalamic neurons: mechanisms of sensitivity to temperature. Ann. NY Acad. Sci. 856, 108–115.Search in Google Scholar

Boulant, J.A. (2000). Role of the preoptic-anterior hypothalamus in thermoregulation and fever. Clin. Infect. Dis. 31, S157–S161.Search in Google Scholar

Boulant, J.A. and Dean, J.B. (1986). Temperature receptors in the central nervous system. Annu. Rev. Physiol. 48, 639–654.Search in Google Scholar

Boulant, J.A. and Gonzalez, R.R. (1977). The effect of skin temperature on the hypothalamic control of heat loss and heat production. Brain Res. 120, 367–372.Search in Google Scholar

Boulant, J.A. and Hardy, J.D. (1974). The effect of spinal and skin temperatures on the firing rate and thermosensitivity of preoptic neurones. J. Physiol. 240, 639–660.Search in Google Scholar

Brauchi, S., Orio, P., and Latorre, R. (2004). Clues to understanding cold sensation: thermodynamics and electrophysiological analysis of the cold receptor TRPM8. Proc. Nat. Acad. Sci. USA 101, 15494–15499.Search in Google Scholar

Brauchi, S., Orta, G., Salazar, M., Rosenmann, E. and Latorre, R. (2006). A hot-sensing cold receptor: C-terminal domain determines thermosensation in transient receptor potential channels. J. Neurosci. 26, 4835–4840.Search in Google Scholar

Brooks, J.C., Nurmikko, T.J., Bimson, W.E., Singh, K.D., and Roberts, N. (2002). fMRI of thermal pain: effects of stimulus laterality and attention. NeuroImage 15, 293–301.Search in Google Scholar

Campbell, J.N. and LaMotte, R.H. (1983). Latency to detection of first pain. Brain Res. 266, 203–208.Search in Google Scholar

Carpenter, D.O. (1967). Temperature effects on pacemaker generation, membrane potential, and critical firing threshold in aplysia neurons. J. Gen. Physiol. 50, 1469–1484.Search in Google Scholar

Caterina, M.J., Schumacher, M.A., Tominaga, M., Rosen, T.A., Levine, J.D., and Julius, D. (1997). The capsaicin receptor: a heat-activated ion channel in the pain pathway. Nature 389, 816–824.Search in Google Scholar

Caterina, M.J., Rosen, T.A., Tominaga, M., Brake, A.J., and Julius, D. (1999). A capsaicin-receptor homologue with a high threshold for noxious heat. Nature 398, 436–441.Search in Google Scholar

Chen, X., Hosono, T., Yoda, T., Fukuda, Y., and Kanosue, K. (1998). Efferent projection from the preoptic area for the control of non-shivering thermogenesis in rats. J. Physiol. 512, 883–892.Search in Google Scholar

Chowdhury, S., Jarecki, B.W., and Chanda, B. (2014). A molecular framework for temperature-dependent gating of ion channels. Cell 158, 1148–1158.Search in Google Scholar

Chung, M.K., Guler, A.D., and Caterina, M.J. (2005). Biphasic currents evoked by chemical or thermal activation of the heat-gated ion channel, TRPV3. J. Biol. Chem. 280, 15928–15941.Search in Google Scholar

Clapham, D.E. (2003). TRP channels as cellular sensors. Nature 426, 517–524.Search in Google Scholar

Clapham, D.E. and Miller, C. (2011). A thermodynamic framework for understanding temperature sensing by transient receptor potential (TRP) channels. Proc. Nat. Acad. Sci. USA 108, 19492–19497.Search in Google Scholar

Clapham, D.E., Runnels, L.W., and Strübing, C. (2001). The TRP ion channel family. Nat. Rev. Neurosci. 2, 387–396.Search in Google Scholar

Cosens, D., and Manning, A. (1969). Abnormal electroretinogram from a Drosophila mutant. Nature 224, 285–287.Search in Google Scholar

Craig, A.D. (2002). How do you feel? Interoception: the sense of the physiological condition of the body. Nat. Rev. Neurosci. 3, 655–666.Search in Google Scholar

Craig, A. (2003). A new view of pain as a homeostatic emotion. Trends Neurosci. 26, 303–307.Search in Google Scholar

Craig, A.D. and Bushnell, M.C. (1994). The thermal grill illusion: unmasking the burn of cold pain. Science 265, 252–255.Search in Google Scholar

Craig, A.D. and Dostrovsky, J.O. (2001). Differential projections of thermoreceptive and nociceptive lamina I trigeminothalamic and spinothalamic neurons in the cat. J. Neurophysiol. 86, 856–870.Search in Google Scholar

Craig, A., Reiman, E., Evans, A., and Bushnell, M. (1996). Functional imaging of an illusion of pain. Nature 384, 258–260.Search in Google Scholar

Craig, A.D., Chen, K., Bandy, D., and Reiman, E.M. (2000). Thermosensory activation of insular cortex. Nat. Neurosci. 3, 184–190.Search in Google Scholar

Davis, K.D. and Pope, G.E. (2002). Noxious cold evokes multiple sensations with distinct time courses. Pain 98, 179–185.Search in Google Scholar

Davis, K.D., Lozano, R.M., Manduch, M., Tasker, R.R., Kiss, Z.H., and Dostrovsky, J.O. (1999). Thalamic relay site for cold perception in humans. J. Neurophysiol. 81, 1970–1973.Search in Google Scholar

Davis, J.B., Gray, J., Gunthorpe, M.J., Hatcher, J.P., Davey, P.T., Overend, P., Harries MH, Latcham J, Clapham C, Atkinson, K., et al. (2000). Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia. Nature 405, 183–187.Search in Google Scholar

del Camino, D., Murphy, S., Heiry, M., Barrett, L.B., Earley, T.J., Cook, C.A., Petrus, MJ., Zhao, M., D’Amours, M., Deering, N., et al. (2010). TRPA1 contributes to cold hypersensitivity. J. Neurosci. 30, 15165–15174.Search in Google Scholar

Dhaka, A., Earley, T.J., Watson, J., and Patapoutian, A. (2008). Visualizing cold spots: TRPM8-expressing sensory neurons and their projections. J. Neurosci. 28, 566–575.Search in Google Scholar

Frank, D.D., Jouandet, G.C., Kearney, P.J., Macpherson, L.J., and Gallio, M. (2015). Temperature representation in the drosophila brain. Nature 519, 358–361.Search in Google Scholar

Gallio, M., Ofstad, T.A., Macpherson, L.J., Wang, J.W., and Zuker, C.S. (2011). The coding of temperature in the drosophila brain. Cell 144, 614–624.Search in Google Scholar

Grandl, J., Hu, H., Bandell, M., Bursulaya, B., Schmidt, M., Petrus, M., and Patapoutian, A. (2008). Pore region of TRPV3 ion channel is specifically required for heat activation. Nat. Neurosci. 11, 1007–1013.Search in Google Scholar

Guler, A.D., Lee, H., Iida, T., Shimizu, I., Tominaga, M., and Caterina, M. (2002). Heat-evoked activation of the ion channel, TRPV4. J. Neurosci. 22, 6408–6414.Search in Google Scholar

Halvorson, I. and Thornhill, J. (1993). Posterior hypothalamic stimulation of anesthetized normothermic and hypothermic rats evokes shivering thermogenesis. Brain Res. 610, 208–215.Search in Google Scholar

Han, Z., Zhang, E., and Craig, A. (1998). Nociceptive and thermoreceptive lamina I neurons are anatomically distinct. Nat. Neurosci. 1, 218–225.Search in Google Scholar

Hardie, R.C., Martin, F., Cochrane, G., Juusola, M., Georgiev, P., and Raghu, P. (2002). Molecular basis of amplification in drosophila phototransduction: roles for G protein, phospholipase C, and diacylglycerol kinase. Neuron 36, 689–701.Search in Google Scholar

Hensel, H. and Zotterman, Y. (1951). The response of the cold receptors to constant cooling. Acta Physiol. Scand. 22, 96–105.Search in Google Scholar

Hille, B. (2001). Ion Channels of Excitable Membranes (Sunderland, MA: Sinauer).Search in Google Scholar

Holstege, G. (1988). Direct and indirect pathways to lamina I in the medulla oblongata and spinal cord of the cat. Progr. Brain Res. 77, 47–94.Search in Google Scholar

Hori, A., Minato, K., and Kobayashi, S. (1999). Warming-activated channels of warm-sensitive neurons in rat hypothalamic slices. Neurosci. Lett. 275, 93–96.Search in Google Scholar

Irie, K., Shimomura, T., and Fujiyoshi, Y. (2012). The C-terminal helical bundle of the tetrameric prokaryotic sodium channel accelerates the inactivation rate. Nat. Commun. 3, 793.Search in Google Scholar

Jiang, Y., Lee, A., Chen, J., Cadene, M., Chait, B.T., and MacKinnon, R. (2002). Crystal structure and mechanism of a calcium-gated potassium channel. Nature 417, 515–522.Search in Google Scholar

Kenshalo, D.R., Holmes, C.E., and Wood, P.B. (1968). Warm and cool thresholds as a function of rate of stimulus temperature change. Percept. Psychophys. 3, 81–84.Search in Google Scholar

LaMotte, R.H. and Campbell, J.N. (1978). Comparison of responses of warm and nociceptive C-fiber afferents in monkey with human judgments of thermal pain. J. Neurophysiol. 41, 509–528.Search in Google Scholar

Lee, H.M., Cho, C.K., Yun, M.H., and Lee, M.W. (1998). Development of a temperature control procedure for a room air-conditioner using the concept of just noticeable difference (JND) in thermal sensation. Int. J. Ind. Ergonom. 22, 207–216.Search in Google Scholar

Lenz, F.A., Seike, M., Richardson, R.T., Lin, Y.C., Baker, F.H., Khoja, I., Jaeger, C.J., Gracely, R.H. (1993). Thermal and pain sensations evoked by microstimulation in the area of human ventrocaudal nucleus. J. Neurophysiol. 70, 200–212.Search in Google Scholar

Lv, Y. and Liu, J. (2007). Effect of transient temperature on thermoreceptor response and thermal sensation. Build. Environ. 42, 656–664.Search in Google Scholar

Mackenzie, R.A., Burke, D., Skuse, N.F., and Lethlean, A.K. (1975). Fibre function and perception during cutaneous nerve block. J. Neurol. Neurosurg. 38, 865–873.Search in Google Scholar

Maingret, F., Lauritzen, I., Patel, A.J., Heurteaux, C., Reyes, R., Lesage, F., Lazdunski, M., Honore, E. (2000). TREK-1 is a heat-activated background K+ channel. EMBO J. 19, 2483–2491.Search in Google Scholar

McKemy, D.D., Neuhausser, W.M., and Julius, D. (2002). Identification of a cold receptor reveals a general role for TRP channels in thermosensation. Nature 416, 52–58.Search in Google Scholar

Mezey, É, Tóth, Z.E., Cortright, D.N., Arzubi, M.K., Krause, J.E., Elde, R., Guo, A., Blumberg, P.M., Szallasi, A. (2000). Distribution of mRNA for vanilloid receptor subtype 1 (VR1), and VR1-like immunoreactivity, in the central nervous system of the rat and human. Proc. Natl. Acad. Sci. USA 97, 3655–3660.Search in Google Scholar

Minke, B. and Cook, B. (2002). TRP channel proteins and signal transduction. Physiol. Rev. 82, 429–472.Search in Google Scholar

Mio, K., Mio, M., Arisaka, F., Sato, M., and Sato, C. (2010). The C-terminal coiled-coil of the bacterial voltage-gated sodium channel NaChBac is not essential for tetramer formation, but stabilizes subunit-to-subunit interactions. Prog. Biophys. Mol. Biol. 103, 111–121.Search in Google Scholar

Montell, C., Birnbaumer, L., and Flockerzi, V. (2002). The TRP channels, a remarkably functional family. Cell 108, 595–598.Search in Google Scholar

Mower, G.D. (1976). Perceived intensity of peripheral thermal stimuli is independent of internal body temperature. J. Comp. Physiol. 90, 1152.Search in Google Scholar

Nagashima, K., Nakai, S., Tanaka, M., and Kanosue, K. (2000). Neuronal circuitries involved in thermoregulation. Auton. Neurosci. 85, 18–25.Search in Google Scholar

Nagy, I. and Rang, H. (1999). Noxious heat activates all capsaicin-sensitive and also a sub-population of capsaicin-insensitive dorsal root ganglion neurons. Neuroscience 88, 995–997.Search in Google Scholar

Nilius, B., Talavera, K., Owsianik, G., Prenen, J., Droogmans, G., and Voets, T. (2005). Gating of TRP channels: a voltage connection? J. Physiol. 567, 35–44.Search in Google Scholar

Patapoutian, A., Peier, A.M., Story, G.M., and Viswanath, V. (2003). ThermoTRP channels and beyond: mechanisms of temperature sensation. Nat. Rev. Neurosci. 4, 529–539.Search in Google Scholar

Payandeh, J. and Minor, D.L. (2015). Bacterial voltage-gated sodium channels (BacNaVs) from the soil, sea, and salt lakes enlighten molecular mechanisms of electrical signaling and pharmacology in the brain and heart. J. Mol. Biol. 427, 3–30.Search in Google Scholar

Pedersen, S.F., Owsianik, G., and Nilius, B. (2005). TRP channels: an overview. Cell Calcium 38, 233–252.Search in Google Scholar

Peier, A.M., Reeve, A.J., Andersson, D.A., Moqrich, A., Earley, T.J., Hergarden, A.C., Story, G.M., Colley, S., Hogenesch, J.B., McIntyre, P., et al. (2002). A heat-sensitive TRP channel expressed in keratinocytes. Science 296, 2046–2049.Search in Google Scholar

Pierau, F., Torrey, P., and Carpenter, D.O. (1974). Mammalian cold receptor afferents: role of an electrogenic sodium pump in sensory transduction. Brain Res. 73, 156–160.Search in Google Scholar

Pioletti, M., Findeisen, F., Hura, G.L., and Minor, D.L. (2006). Three-dimensional structure of the KChIP1–Kv4. 3 T1 complex reveals a cross-shaped octamer. Nat. Struct. Mol. Biol. 13, 987–995.Search in Google Scholar

Powl, A.M., O’Reilly, A.O., Miles, A.J., and Wallace, B.A. (2010). Synchrotron radiation circular dichroism spectroscopy-defined structure of the C-terminal domain of NaChBac and its role in channel assembly. Proc. Nat. Acad. Sci. USA 107, 14064–14069.Search in Google Scholar

Price, D.D., Hu, J.W., Dubner, R., and Gracely, R.H. (1977). Peripheral suppression of first pain and central summation of second pain evoked by noxious heat pulses. Pain 3, 57–68.Search in Google Scholar

Price, D.D., Hayes, R.L., Ruda, M., and Dubner, R. (1978). Spatial and temporal transformations of input to spinothalamic tract neurons and their relation to somatic sensations. J. Neurophysiol. 41, 933–947.Search in Google Scholar

Rhee, S.G., and Bae, Y.S. (1997). Regulation of phosphoinositide-specific phospholipase C isozymes. J. Biol. Chem. 272, 15045–15048.Search in Google Scholar

Satinoff, E. (1978). Neural organization and evolution of thermal regulation in mammals. Science 201, 16–22.Search in Google Scholar

Schepers, R.J. and Ringkamp, M. (2010). Thermoreceptors and thermosensitive afferents. Neurosci. Biobehav. Rev. 34, 177–184.Search in Google Scholar

Shaya, D., Findeisen, F., Abderemane-Ali, F., Arrigoni, C., Wong, S., Nurva, S.R., Loussouarn, G., Minor, D.L. (2014). Structure of a prokaryotic sodium channel pore reveals essential gating elements and an outer ion binding site common to eukaryotic channels. J. Mol. Biol. 426, 467–483.Search in Google Scholar

Smith, G., Gunthorpe, M., Kelsell, R., Hayes, P., Reilly, P., Facer, P., Wright, J.E., Jerman, J.C., Walhin, J.P., Ooi, L. (2002). TRPV3 is a temperature-sensitive vanilloid receptor-like protein. Nature 418, 186–190.Search in Google Scholar

Souslova, V., Cesare, P., Ding, Y., Akopian, A.N., Stanfa, L., Suzuki, R., Carpenter, K., Dickenson, A., Boyce, S., Hill, R., et al. (2000). Warm-coding deficits and aberrant inflammatory pain in mice lacking P2X 3 receptors. Nature 407, 1015–1017.Search in Google Scholar

Story, G.M., Peier, A.M., Reeve, A.J., Eid, S.R., Mosbacher, J., Hricik, T.R., McIntyre, P., Jegla, T., Bevan, S., Patapoutian, A., et al. (2003). ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell 112, 819–829.Search in Google Scholar

Stuart, D., Kawamura, Y., and Hemingway, A. (1961). Activation and suppression of shivering during septal and hypothalamic stimulation. Exp. Neurol. 4, 485–506.Search in Google Scholar

Tillman, D., Treede, R., Meyer, R.A., and Campbell, J.N. (1995). Response of C fibre nociceptors in the anaesthetized monkey to heat stimuli: estimates of receptor depth and threshold. J. Physiol. 485, 753–765.Search in Google Scholar

Torvi, D. and Dale, J. (1994). A finite element model of skin subjected to a flash fire. J. Biomech. Eng 116, 250–255.Search in Google Scholar

Treede, R., Meyer, R., Raja, S., and Campbell, J. (1995). Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin. J. Physiol. 483, 747–758.Search in Google Scholar

Voets, T., Droogmans, G., Wissenbach, U., Janssens, A., Flockerzi, V., and Nilius, B. (2004). The principle of temperature-dependent gating in cold-and heat-sensitive TRP channels. Nature 430, 748–754.Search in Google Scholar

Voets, T., Talavera, K., Owsianik, G., and Nilius, B. (2005). Sensing with TRP channels. Nat. Chem. Biol. 1, 85–92.Search in Google Scholar

Vriens, J., Nilius, B., and Voets, T. (2014). Peripheral thermosensation in mammals. Nat. Rev. Neurosci. 15, 573–589.Search in Google Scholar

Watanabe, H., Vriens, J., Suh, S. H., Benham, C.D., Droogmans, G., and Nilius, B. (2002). Heat-evoked activation of TRPV4 channels in a HEK293 cell expression system and in native mouse aorta endothelial cells. J. Biol. Chem. 277, 47044–47051.Search in Google Scholar

Xu, H., Ramsey, I.S., Kotecha, S.A., Moran, M.M., Chong, J.A., Lawson, D., Ge, P., Lilly, J., Silos-Santiago, I., Xie, Y., et al. (2002). TRPV3 is a calcium-permeable temperature-sensitive cation channel. Nature 418, 181–186.Search in Google Scholar

Yarnitsky, D. and Ochoa, J.L. (1990). Release of cold-induced burning pain by block of cold-specific afferent input. Brain 113, 893–902.Search in Google Scholar

Yu, F.H., Yarov-Yarovoy, V., Gutman, G.A., and Catterall, W.A. (2005). Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol. Rev. 57, 387–395.Search in Google Scholar

Yuan, P., Leonetti, M.D., Pico, A.R., Hsiung, Y., and MacKinnon, R. (2010). Structure of the human BK channel Ca2+-activation apparatus at 3.0 Å resolution. Science 329, 182–186.Search in Google Scholar

Zagotta, W.N., Olivier, N.B., Black, K.D., Young, E.C., Olson, R., and Gouaux, E. (2003). Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 425, 200–205.Search in Google Scholar

Zhang, Y., Yanase-Fujiwara, M., Hosono, T., and Kanosue, K. (1995). Warm and cold signals from the preoptic area: which contribute more to the control of shivering in rats? J. Physiol. 485, 195–202.Search in Google Scholar

Zhang, E., Han, Z., and Craig, A. (1996). Morphological classes of spinothalamic lamina I neurons in the cat. J. Comp. Neurol. 367, 537–549.Search in Google Scholar

Zhang, Y., Hoon, M.A., Chandrashekar, J., Mueller, K.L., Cook, B., Wu, D., Zuker, C.S., Ryba, N.J. (2003). Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways. Cell 112, 293–301.Search in Google Scholar

Received: 2016-6-30
Accepted: 2016-8-7
Published Online: 2016-10-18
Published in Print: 2017-1-1

©2017 Walter de Gruyter GmbH, Berlin/Boston