In the peripheral nervous system, somatosensory neurons report a wide range of temperatures, from noxious heat to noxious cold. We know that distinct subsets of nerve fibers will respond to specific temperature thresholds, presumably based upon the thermosensory molecules they express. Moreover, these nerves are key players in the detection of painful, tissue damaging stimuli. We have recently begun to grasp how these nerve fibers detect temperature due to the identification of molecules that respond to distinct thermal stimuli. These molecules, members of the transient receptor potential (TRP) channel family, were identified by their sensitivity to compounds, such as capsaicin and menthol, which mimic distinct psychophysical sensations. Taken together, these thermosensors can detect the broad range of temperatures we perceive and provides a molecular explanation for how temperature is detected. Nonetheless, our understanding of the cellular transduction mechanisms that mediate and regulate these thermosensors remains limited. Therefore, we are analyzing the sensory afferents expressing the cold and menthol receptor, TRPM8, to further our characterization of the transduction mechanisms mediating cold sensation. To this end, we have generated transgenic mice that express a fluorescent label specifically in TRPM8-positive sensory neurons that is detectable in vivo. With this animal model, we are investigating the peripheral projections of cold-sensitive afferents, the mechanisms of cold adaptation in native cells, and the in vivo role of these neurons in somatosensation.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Somatosensory and Chemosensory Systems Study Section (SCS)
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Gnadt, James W
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University of Southern California
Schools of Dentistry
Los Angeles
United States
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McCoy, Daniel D; Zhou, Ligang; Nguyen, Anh-Khoi et al. (2013) Enhanced insulin clearance in mice lacking TRPM8 channels. Am J Physiol Endocrinol Metab 305:E78-88
Knowlton, Wendy M; Palkar, Radhika; Lippoldt, Erika K et al. (2013) A sensory-labeled line for cold: TRPM8-expressing sensory neurons define the cellular basis for cold, cold pain, and cooling-mediated analgesia. J Neurosci 33:2837-48
Osborne, Melissa; Gomez, Daniel; Feng, Zhihua et al. (2012) Characterization of behavioral and neuromuscular junction phenotypes in a novel allelic series of SMA mouse models. Hum Mol Genet 21:4431-47
Knowlton, Wendy M; McKemy, David D (2011) TRPM8: from cold to cancer, peppermint to pain. Curr Pharm Biotechnol 12:68-77
McCoy, Daniel D; Knowlton, Wendy M; McKemy, David D (2011) Scraping through the ice: uncovering the role of TRPM8 in cold transduction. Am J Physiol Regul Integr Comp Physiol 300:R1278-87
Knowlton, Wendy M; Daniels, Richard L; Palkar, Radhika et al. (2011) Pharmacological blockade of TRPM8 ion channels alters cold and cold pain responses in mice. PLoS One 6:e25894
Knowlton, Wendy M; Bifolck-Fisher, Amber; Bautista, Diana M et al. (2010) TRPM8, but not TRPA1, is required for neural and behavioral responses to acute noxious cold temperatures and cold-mimetics in vivo. Pain 150:340-50
Takashima, Y; Ma, L; McKemy, D D (2010) The development of peripheral cold neural circuits based on TRPM8 expression. Neuroscience 169:828-42
Carr, Richard W; Pianova, Svetlana; McKemy, David D et al. (2009) Action potential initiation in the peripheral terminals of cold-sensitive neurones innervating the guinea-pig cornea. J Physiol 587:1249-64
Mandadi, S; Nakanishi, S T; Takashima, Y et al. (2009) Locomotor networks are targets of modulation by sensory transient receptor potential vanilloid 1 and transient receptor potential melastatin 8 channels. Neuroscience 162:1377-97

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