TRPM8 Is Required for Cold Sensation in Mice

Dhaka, Ajay; Murray, Amber N.; Mathur, Jayanti; Earley, Taryn J.; Petrus, Matt; Patapoutian, Ardem

doi:10.1016/j.neuron.2007.02.024

Cited by 801 publications

(874 citation statements)

References 35 publications

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“…Second, we found that mouse primary somatosensory forepaw cortex (S1) is necessary for thermal perception. Third, the TRPM8 cold receptor protein was necessary for mild cold temperature perception, suggesting that cold avoidance behaviors that are impaired in Trpm8 -/-mutant mice could be a result of a lack of fine temperature perception [4][5][6] . Finally, our primary sensory nerve recordings identified polymodal C fibers with low thresholds for cooling as the likely drivers for fine cooling perception in mice.…”

Section: Discussionmentioning

confidence: 99%

“…It is now well established that the TRPM8 ion channel present in sensory afferents is an important transducer of cold [4][5][6]27 . We found that Trpm8 -/-12 mutant mice are incapable of perceiving mild cold and this lack of behavior is correlated with the loss of cold-evoked activity in cortical L2/3 neurons.…”

Section: Discussionmentioning

confidence: 99%

“…Transient receptor potential melastatin 8 (TRPM8) has been identified as an ion channel receptor protein that mediates cold transduction in sensory afferent neurons that innervate the skin 26,27 and is involved in cold avoidance behavior in mice [4][5][6]22 . Whole-cell patch clamp recordings from L2/3 cortical neurons in forepaw S1 in anaesthetized Trpm8 -/-and Trpm8 +/+ littermate control mice during cold thermal stimulation of the forepaw revealed that six of eight neurons in Trpm8 +/+ mice showed a subthreshold response to cooling.…”

Section: Cooling Perception Involves Trpm8mentioning

confidence: 99%

“…Two-plate thermal preference arenas have shown that mice avoid cooler floor temperatures [4][5][6] , but this test has limited spatial and temporal control of the stimulus and lacks fine-grained resolution for near threshold perception. We therefore developed a shortlatency, goal-directed thermal perception task using the glabrous skin of the mouse forepaw.…”

Section: Introductionmentioning

confidence: 99%

“…Our data suggest that S1 is critical for thermal perception in mice, but do not exclude a role of insular cortex for thermal processing. Indeed, in rodents, a secondary somatosensory representation is located in insular cortex 44 .It is now well established that the TRPM8 ion channel present in sensory afferents is an important transducer of cold [4][5][6]27 . We found that Trpm8 -/-12 mutant mice are incapable of perceiving mild cold and this lack of behavior is correlated with the loss of cold-evoked activity in cortical L2/3 neurons.…”

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A somatosensory circuit for cooling perception in mice

et al. 2014

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The temperature of an object provides important somatosensory information for animals performing tactile tasks. Humans can perceive skin cooling of less than one degree, but the sensory afferents and central circuits they engage to enable the perception of surface temperature are poorly understood. To address these questions, we examined the perception of glabrous skin cooling in mice. We found that mice were also capable of perceiving small amplitude skin cooling and that primary somatosensory (S1) cortical neurons were required for cooling perception. Moreover, the absence of the menthol-gated transient receptor potential melastatin 8 ion channel in sensory afferent fibers eliminated the ability to perceive cold and the corresponding activation of S1 neurons. Our results identify parts of a neural circuit underlying cold perception in mice and provide a new model system for the analysis of thermal processing and perception and multimodal integration.An accurate sense of surface temperature helps animals to perceive object structure and identity. Psychophysical experiments have shown that humans are able to perceive tiny changes in skin cooling with a range between 0.4 and 1.8 ˚C 1,2 . It has, however, proved challenging to assess the perceptual ability of rodents to discriminate small temperature steps at threshold levels.Classical paw withdrawal tests cannot differentiate between reflexive avoidance behavior and sensory perception 3 . Two-plate thermal preference arenas have shown that mice avoid cooler floor temperatures [4][5][6] , but this test has limited spatial and temporal control of the stimulus and lacks fine-grained resolution for near threshold perception. We therefore developed a shortlatency, goal-directed thermal perception task using the glabrous skin of the mouse forepaw.A general dogma is that all somatosensory input, including thermal, is integrated by the primary somatosensory cortex (S1) to form a coherent sensory percept. S1 is necessary for tactile somatosensory perception in rodents [7][8][9][10][11][12][13] . The role of S1 in thermal perception, however, is under debate, 3 with three studies concluding that rodent S1 is not involved [14][15][16] and another concluding that it is 17 . This may be because these studies used large cortical lesions with long recovery and retraining periods in freely moving rats that used facial regions to detect temperature [14][15][16][17] .Likewise, very little is known about the underlying cortical neural processing of non-noxious thermal stimuli in rodents. To the best of our knowledge, only one study, conducted in anesthetized rats stimulating scrotal skin, has shown extracellular responses of cortical neurons to thermal stimulation 18 . At the sensory periphery, a range of primary afferents including myelinated Aβ mechanoreceptors 2,19 , thinly myelinated Aδ-fibers and unmyelinated polymodal C fibers, fire during skin cooling 4,20,21 . Although it is thought that thickly myelinated Aδ fibers are responsible for cooling perception, C fibers ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Cooling Perception Involves Trpm8mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

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A somatosensory circuit for cooling perception in mice

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Thermosensation

Mak

Zhang

McNaughton

2009

Encyclopedia of Life Sciences

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Detection of temperature, both of the surroundings and of the body itself, is critical for maintaining normal physiological functioning. To date, a number of thermo‐sensitive ion channels have been reported to be involved in thermosensation, six of which belong to the transient receptor potential (TRP) superfamily of nonselective cation channels. Each of these operates over a distinct temperature range and many respond to natural compounds that elicit sensations of heat or cold. The best studied is TRP vanilloid 1 (TRPV1), which is both a receptor for capsaicin, the active principle of chilli peppers, and a painful heat receptor which responds to temperatures over 42°C. Our understanding of cold transduction has also rapidly increased in recent years with the intriguing discovery of the cold receptors TRP melastatin 8 (TRPM8) and TRP ankyrin 1 (TRPA1). Key concepts Our current understanding of thermosensation comes mainly from the identification of six temperature‐sensitive ion channels (thermo‐TRP channels) belonging to the transient receptor potential (TRP) superfamily of nonselective calcium channels. Each thermo‐TRP operates over a distinct temperature range. Four of them (TRPV1–4) are activated by heat, and two of them (TRPM8 and TRPA1) are activated by cold. Thermo‐TRPs also respond to natural compounds that elicit corresponding psychophysical sensations of heat or cold. The response of these channels is regulated after tissue damage and is subjected to modulation by inflammatory mediators released at the site of injury. The altered sensitivity of these channels accounts for the phenomenon of thermal hyperalgesia. Inflammatory mediators sensitize TRPV1 via the activation of protein kinases such as protein kinase C (PKC), protein kinase A (PKA) and Src. The modulation of TRPV1 by PKC and PKA depends on the correct positioning of the kinases by a scaffolding protein, AKAP79/150. There are other possible mechanisms involved in thermosensation, for example, modulation of potassium channels such as TREK‐2.

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Ion Channels

Lipscombe¹,

Toro²

2021

Encyclopedia of Life Sciences

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Ion channels are membrane proteins that create specialised routes for ions to cross cell membrane lipid bilayers with high selectivity and at relatively high speeds. All cells of all organisms use ion channels to control a range of functions. The majority of electrical membrane signals originate from the flow of select ions through ion channels. Cellular control of ion channel activity is critical for unicellular and multicellular organisms to respond to their environments. Avoiding external threats, seeking nutrients, adapting to normal developmental processes, creating memories and modifying outputs according to previous events all involve ion channel activity. Ion channel dysfunction underlies multiple human disorders and diseases: developmental disorders, pain syndromes that include extreme pain as well as congenital indifference to pain, certain types of migraines, epilepsies, ataxias, paralyses, cardiac arrhythmias, developmental disorders, psychiatric illness, male infertility, immunodeficiency and renal failure can all be due to malfunctioning ion channels. Thus, ion channels are critically important drug targets for the treatment of a great many illnesses and disorders in multiple organs and body systems. Key Concepts Ion channels are found in all living cells. Ion channels create specialised routes for ions to cross biological cell membranes. Ion concentration gradients create ion driving forces that regulate membrane potential. Ion channels are gated (opened and closed) by a wide range of biological signals. Ion channels are selectively permeable to specific ions. A range of extracellular, intracellular and membrane signals alter the activity of ion channels. Abnormal ion channel function underlies many disorders and diseases.

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TRPM8 Is Required for Cold Sensation in Mice

Cited by 801 publications

References 35 publications

A somatosensory circuit for cooling perception in mice

A somatosensory circuit for cooling perception in mice

Thermosensation

Ion Channels

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