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Pharmacological Blockade of TRPM8 Ion Channels Alters Cold and Cold Pain Responses in Mice

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      Abstract

      TRPM8 ( Transient Receptor Potential Melastatin-8) is a cold- and menthol-gated ion channel necessary for the detection of cold temperatures in the mammalian peripheral nervous system. Functioning TRPM8 channels are required for behavioral responses to innocuous cool, noxious cold, injury-evoked cold hypersensitivity, cooling-mediated analgesia, and thermoregulation. Because of these various roles, the ability to pharmacologically manipulate TRPM8 function to alter the excitability of cold-sensing neurons may have broad impact clinically. Here we examined a novel compound, PBMC (1-phenylethyl-4-(benzyloxy)-3-methoxybenzyl(2-aminoethyl)carbamate) which robustly and selectively inhibited TRPM8 channels in vitro with sub-nanomolar affinity, as determined by calcium microfluorimetry and electrophysiology. The actions of PBMC were selective for TRPM8, with no functional effects observed for the sensory ion channels TRPV1 and TRPA1. PBMC altered TRPM8 gating by shifting the voltage-dependence of menthol-evoked currents towards positive membrane potentials. When administered systemically to mice, PBMC treatment produced a dose-dependent hypothermia in wildtype animals while TRPM8-knockout mice remained unaffected. This hypothermic response was reduced at lower doses, whereas responses to evaporative cooling were still significantly attenuated. Lastly, systemic PBMC also diminished cold hypersensitivity in inflammatory and nerve-injury pain models, but was ineffective against oxaliplatin-induced neuropathic cold hypersensitivity, despite our findings that TRPM8 is required for the cold-related symptoms of this pathology. Thus PBMC is an attractive compound that serves as a template for the formulation of highly specific and potent TRPM8 antagonists that will have utility both in vitro and in vivo.

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      Most cited references 49

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      The capsaicin receptor: a heat-activated ion channel in the pain pathway.

      Capsaicin, the main pungent ingredient in 'hot' chilli peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. We have used an expression cloning strategy based on calcium influx to isolate a functional cDNA encoding a capsaicin receptor from sensory neurons. This receptor is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. The cloned capsaicin receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo.
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        Identification of a cold receptor reveals a general role for TRP channels in thermosensation.

        The cellular and molecular mechanisms that enable us to sense cold are not well understood. Insights into this process have come from the use of pharmacological agents, such as menthol, that elicit a cooling sensation. Here we have characterized and cloned a menthol receptor from trigeminal sensory neurons that is also activated by thermal stimuli in the cool to cold range. This cold- and menthol-sensitive receptor, CMR1, is a member of the TRP family of excitatory ion channels, and we propose that it functions as a transducer of cold stimuli in the somatosensory system. These findings, together with our previous identification of the heat-sensitive channels VR1 and VRL-1, demonstrate that TRP channels detect temperatures over a wide range and are the principal sensors of thermal stimuli in the mammalian peripheral nervous system.
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          Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1.

          Wasabi, horseradish and mustard owe their pungency to isothiocyanate compounds. Topical application of mustard oil (allyl isothiocyanate) to the skin activates underlying sensory nerve endings, thereby producing pain, inflammation and robust hypersensitivity to thermal and mechanical stimuli. Despite their widespread use in both the kitchen and the laboratory, the molecular mechanism through which isothiocyanates mediate their effects remains unknown. Here we show that mustard oil depolarizes a subpopulation of primary sensory neurons that are also activated by capsaicin, the pungent ingredient in chilli peppers, and by Delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana. Both allyl isothiocyanate and THC mediate their excitatory effects by activating ANKTM1, a member of the TRP ion channel family recently implicated in the detection of noxious cold. These findings identify a cellular and molecular target for the pungent action of mustard oils and support an emerging role for TRP channels as ionotropic cannabinoid receptors.
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            Author and article information

            Affiliations
            [1 ]Neurobiology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America
            [2 ]Molecular and Computational Biology Section, Department of Biological Sciences, University of Southern California, Los Angeles, California, United States of America
            [3 ]Neuroscience Graduate Program, University of Southern California, Los Angeles, California, United States of America
            Georgia State University, United States of America
            Author notes

            Conceived and designed the experiments: WMK RLD D. McKemy. Performed the experiments: WMK RLD RP D. McCoy. Analyzed the data: WMK RLD RP D. McKemy. Contributed reagents/materials/analysis tools: WMK RLD RP D. McCoy D. McKemy. Wrote the paper: WMK RLD RP D. McKemy.

            [¤]

            Current address: Biology Department, College of Idaho, Caldwell, Idaho, United States of America

            Contributors
            Role: Editor
            Journal
            PLoS One
            plos
            plosone
            PLoS ONE
            Public Library of Science (San Francisco, USA )
            1932-6203
            2011
            30 September 2011
            : 6
            : 9
            3184174
            21984952
            PONE-D-11-14193
            10.1371/journal.pone.0025894
            (Editor)
            Knowlton et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
            Counts
            Pages: 13
            Categories
            Research Article
            Biology
            Anatomy and Physiology
            Neurological System
            Sensory Physiology
            Computational Biology
            Computational Neuroscience
            Sensory Systems
            Immunology
            Immunity
            Inflammation
            Microbiology
            Immunity
            Inflammation
            Neuroscience
            Cellular Neuroscience
            Ion Channels
            Cognitive Neuroscience
            Pain
            Computational Neuroscience
            Sensory Systems
            Neurophysiology
            Peripheral Nervous System
            Sensory Perception
            Sensory Systems
            Medicine
            Anatomy and Physiology
            Neurological System
            Sensory Physiology
            Sensory Systems
            Clinical Immunology
            Immunity
            Inflammation
            Mental Health
            Psychology
            Sensory Perception
            Social and Behavioral Sciences
            Psychology
            Sensory Perception

            Uncategorized

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