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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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      Most cited references 54

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      Ethical guidelines for investigations of experimental pain in conscious animals.

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        Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer.

        The standard adjuvant treatment of colon cancer is fluorouracil plus leucovorin (FL). Oxaliplatin improves the efficacy of this combination in patients with metastatic colorectal cancer. We evaluated the efficacy of treatment with FL plus oxaliplatin in the postoperative adjuvant setting. We randomly assigned 2246 patients who had undergone curative resection for stage II or III colon cancer to receive FL alone or with oxaliplatin for six months. The primary end point was disease-free survival. A total of 1123 patients were randomly assigned to each group. After a median follow-up of 37.9 months, 237 patients in the group given FL plus oxaliplatin had had a cancer-related event, as compared with 293 patients in the FL group (21.1 percent vs. 26.1 percent; hazard ratio for recurrence, 0.77; P=0.002). The rate of disease-free survival at three years was 78.2 percent (95 percent confidence interval, 75.6 to 80.7) in the group given FL plus oxaliplatin and 72.9 percent (95 percent confidence interval, 70.2 to 75.7) in the FL group (P=0.002 by the stratified log-rank test). In the group given FL plus oxaliplatin, the incidence of febrile neutropenia was 1.8 percent, the incidence of gastrointestinal adverse effects was low, and the incidence of grade 3 sensory neuropathy was 12.4 percent during treatment, decreasing to 1.1 percent at one year of follow-up. Six patients in each group died during treatment (death rate, 0.5 percent). Adding oxaliplatin to a regimen of fluorouracil and leucovorin improves the adjuvant treatment of colon cancer. Copyright 2004 Massachusetts Medical Society
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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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            Author and article information

            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
            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
            3377073
            21438154
            10.1002/emmm.201100134
            Copyright © 2011 EMBO Molecular Medicine
            Categories
            Research Articles

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