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      Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors

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          Abstract

          Cold hypersensitivity is the hallmark of oxaliplatin-induced neuropathy, which develops in nearly all patients under this chemotherapy. To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed. Here, we report that oxaliplatin exaggerates cold perception in mice as well as in patients. These symptoms are mediated by primary afferent sensory neurons expressing the thermoreceptor TRPM8. Mechanistically, oxaliplatin promotes over-excitability by drastically lowering the expression of distinct potassium channels (TREK1, TRAAK) and by increasing the expression of pro-excitatory channels such as the hyperpolarization-activated channels (HCNs). These findings are corroborated by the analysis of TREK1-TRAAK null mice and use of the specific HCN inhibitor ivabradine, which abolishes the oxaliplatin-induced cold hypersensibility. These results suggest that oxaliplatin exacerbates cold perception by modulating the transcription of distinct ionic conductances that together shape sensory neuron responses to cold. The translational and clinical implication of these findings would be that ivabradine may represent a tailored treatment for oxaliplatin-induced neuropathy.

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          Ethical guidelines for investigations of experimental pain in conscious animals.

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            TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents.

            TRPA1 is an excitatory ion channel targeted by pungent irritants from mustard and garlic. TRPA1 has been proposed to function in diverse sensory processes, including thermal (cold) nociception, hearing, and inflammatory pain. Using TRPA1-deficient mice, we now show that this channel is the sole target through which mustard oil and garlic activate primary afferent nociceptors to produce inflammatory pain. TRPA1 is also targeted by environmental irritants, such as acrolein, that account for toxic and inflammatory actions of tear gas, vehicle exhaust, and metabolic byproducts of chemotherapeutic agents. TRPA1-deficient mice display normal cold sensitivity and unimpaired auditory function, suggesting that this channel is not required for the initial detection of noxious cold or sound. However, TRPA1-deficient mice exhibit pronounced deficits in bradykinin-evoked nociceptor excitation and pain hypersensitivity. Thus, TRPA1 is an important component of the transduction machinery through which environmental irritants and endogenous proalgesic agents depolarize nociceptors to elicit inflammatory pain.
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              The menthol receptor TRPM8 is the principal detector of environmental cold.

              Sensory nerve fibres can detect changes in temperature over a remarkably wide range, a process that has been proposed to involve direct activation of thermosensitive excitatory transient receptor potential (TRP) ion channels. One such channel--TRP melastatin 8 (TRPM8) or cold and menthol receptor 1 (CMR1)--is activated by chemical cooling agents (such as menthol) or when ambient temperatures drop below approximately 26 degrees C, suggesting that it mediates the detection of cold thermal stimuli by primary afferent sensory neurons. However, some studies have questioned the contribution of TRPM8 to cold detection or proposed that other excitatory or inhibitory channels are more critical to this sensory modality in vivo. Here we show that cultured sensory neurons and intact sensory nerve fibres from TRPM8-deficient mice exhibit profoundly diminished responses to cold. These animals also show clear behavioural deficits in their ability to discriminate between cold and warm surfaces, or to respond to evaporative cooling. At the same time, TRPM8 mutant mice are not completely insensitive to cold as they avoid contact with surfaces below 10 degrees C, albeit with reduced efficiency. Thus, our findings demonstrate an essential and predominant role for TRPM8 in thermosensation over a wide range of cold temperatures, validating the hypothesis that TRP channels are the principal sensors of thermal stimuli in the peripheral nervous system.
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                Author and article information

                Journal
                EMBO Mol Med
                EMBO Mol Med
                emmm
                EMBO Molecular Medicine
                WILEY-VCH Verlag (Weinheim )
                1757-4676
                1757-4684
                May 2011
                : 3
                : 5
                : 266-278
                Affiliations
                [1 ]simpleDépartement de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle Montpellier, France
                [2 ]simpleINSERM, U661 Montpellier, France
                [3 ]simpleUniversités de Montpellier 1 and 2, UMR-5203 Montpellier, France
                [4 ]simpleClermont Université, Université d'Auvergne, Pharmacologie Fondamentale et Clinique de la Douleur Clermont-Ferrand, France
                [5 ]simpleINSERM, U 766 Clermont-Ferrand, France
                [6 ]simpleInstitut de Pharmacologie Moléculaire et Cellulaire, CNRS, UMR 6097, Université de Nice-Sophia Antipolis, Institut Paul Hamel Sophia Antipolis, Valbonne, France
                [7 ]simpleCHU Clermont-Ferrand Clermont-Ferrand, France
                Author notes
                * Corresponding author: Tel: +33 4 34 35 92 48; Fax: +33 4 67 54 24 32; E-mail: emmanuel.bourinet@ 123456igf.cnrs.fr
                Article
                10.1002/emmm.201100134
                3377073
                21438154
                243e30f5-b3e5-4456-893a-420764b27d28
                Copyright © 2011 EMBO Molecular Medicine
                History
                : 22 June 2010
                : 24 February 2011
                : 28 February 2011
                Categories
                Research Articles

                Molecular medicine
                chemotherapy-induced neuropathy,trpm8,background potassium channels,hyperpolarization activated channels,cold pain

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