Attenuated Cold Sensitivity in TRPM8 Null Mice

Colburn, Raymond W.; Lubin, Mary Lou; Stone, Dennis J.; Wang, Yan; Lawrence, Danielle; D’Andrea, Michael R.; Brandt, Michael R.; Liu, Yi; Flores, Christopher M.; Qin, Ning

doi:10.1016/j.neuron.2007.04.017

Cited by 670 publications

(696 citation statements)

References 33 publications

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“…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: 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

et al. 2014

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“…Small‐diameter primary afferents, C‐fiber and A‐delta, are believed to mediate abnormal temperature sensitivity following nerve injury or neurotoxicity in rats (Colburn et al. 2007; Leith et al. 2010; Xiao et al.…”

Section: Discussionmentioning

confidence: 99%

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

Shidahara

Ogawa

Nakamura

et al. 2016

Pharmacology Res & Perspec

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Oxaliplatin is a first‐line treatment for colorectal cancer. However, shortly following treatment, cold‐evoked hypersensitivity appears in the extremities and over time, the pain is such that oxaliplatin dosing may need to be markedly reduced or even terminated. There is currently a lack of efficacious treatments for oxaliplatin‐induced peripheral neuropathy, which is due in part to the difficulty in translating findings obtained from preclinical rodent models of chemotherapy‐induced peripheral neuropathy. Nonhuman primates (NHP) are phylogenetically closer to humans than rodents and may show drug responses that parallel those of humans. A significant decrease in tail withdrawal latency to 10°C water (“cold hypersensitivity”) was observed beginning 3 days after intravenous infusion of oxaliplatin (5 mg/kg) in Macaca fascicularis. A single treatment of duloxetine (30 mg/kg, p.o.) ameliorated oxaliplatin‐induced cold hypersensitivity, whereas pregabalin (30 mg/kg, p.o.) and tramadol (30 mg/kg, p.o.) did not. By contrast, in rats, no significant cold hypersensitivity, or increased responsiveness to acetone applied to the hind paws, was observed 3 days after the first injection of oxaliplatin (5 mg/kg, i.p., once per day, two injections). Therefore, rats were tested after six treatments of oxaliplatin, 17 days after the first treatment. All analgesics (30 mg/kg, p.o.) significantly ameliorated cold hypersensitivity in rats. The activity of analgesics in the oxaliplatin‐treated macaques parallel clinical findings. The current results indicate that the NHP could serve as a bridge species to improve translatability of preclinical findings into clinically useful treatments for oxaliplatin‐induced peripheral neuropathy.

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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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Attenuated Cold Sensitivity in TRPM8 Null Mice

Cited by 670 publications

References 33 publications

A somatosensory circuit for cooling perception in mice

A somatosensory circuit for cooling perception in mice

Pharmacological comparison of a nonhuman primate and a rat model of oxaliplatin‐induced neuropathic cold hypersensitivity

Thermosensation

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