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Laura POUPON, 1 ère année de thèse U1107 – Pharmacologie fondamentale et clinique de la douleur

Molecular and behavioral exploration of orofacial hypersensitivity in a model of oxaliplatin-chemotherapy induced acute neuropathy. 9ème Symposium National du Réseau Recherche sur la Douleur 22 et 23 mars 2013. Laura POUPON, 1 ère année de thèse

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Laura POUPON, 1 ère année de thèse U1107 – Pharmacologie fondamentale et clinique de la douleur

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  1. Molecular and behavioral exploration of orofacial hypersensitivity in a model of oxaliplatin-chemotherapy induced acute neuropathy 9ème Symposium National du Réseau Recherche sur la Douleur 22 et 23 mars 2013 Laura POUPON, 1ère année de thèse U1107 – Pharmacologie fondamentale et clinique de la douleur Directeur : Pr. A. Eschalier

  2. Oxaliplatin chemotherapy-inducedneuropathy Oxaliplatin (Eloxatin®) Platinum-basedantineoplasic Therapeuticeffects Used in colorectal cancer chemotherapy Inhibits DNA replication by platinumadduct formation Adverse effects Cephalic territory 90% of patients develop acute neuropathy Cold hypersensitivity Numbness at both extracephalic and cephalic territories Dose reduction to limit neuropathic symptoms Extracephalic territory

  3. Existingextracephalicresults in mice Clinical symptoms Mice model Cold hyperalgesia DRG Mechanical hypersensitivity Descoeur et al., 2011

  4. Existingextracephalicresults in mice Mice ion channels transcriptional expression Clinical symptoms DRG DRG Correlationbetweenoxaliplatin-induced cold hypersensitivity andremodelling of ion channel expression in nociceptors Descoeur et al., 2011

  5. Differencesbetweencephalic and extracephalic sensorysystems Sensory systems Extracephalic Cephalic TG DRG A-fibers C-fibers Caudalis ?

  6. Aim of the study Are there behavioral and molecular differences between the cephalic and the extracephalic territories in a murine model of oxaliplatin chemotherapy-induced neuropathy • Developmentof adapted orofacial behavioraltests • Assessmentof ion channel transcriptional plasticity at the TG level • Genetic or pharmacological validation of ion channels as targets of interest ? ?

  7. Material& Methods Mice model Behavioral tests Day Single i.p. injection of oxaliplatin (6mg/kg) Peak pain behaviorat D4 Daily measures of pain scores from D0 to D4 D0 D1 D2 D3 D4 Caudalis -TG HIC (pERK) qPCR (ion channels)

  8. Oral cold perception in WT mice Cold water aversion test 3h 3h 3h 3h 3h 3h D0 D1 D2 D3 D4 4 - 6°C Water consumption(mL) * * Vehicle Oxaliplatin 6 mg/kg D4 - Caudalis Vehicle pERK Oxaliplatin Oral cold Hypersensitivity

  9. Cutaneous cold and Mechanical perception in WT mice Acetone test Brush test Vehicle Oxaliplatin 6 mg/kg *** * Grooming (s) Response to dynamic mechanical stimulation 5 consecutivestrokes Daily measure of grooming behavior On the upper lip area skin surface Vehicle Oxaliplatin 6 mg/kg *** * * Score Mechanical hypersensitivity Cutaneous cold Hypersensitivity

  10. Ion channels plasticity in DRG and TG qPCR Extracephalic (DRG) Vehicle Oxaliplatin Cephalic (TG)

  11. Cold sensors : TRPM8 and TRPA1 NS qPCR Acetone test Brush test TRPM8 -/-mice NS Vehicle Oxaliplatin 6 mg/kg ** ** Grooming (s) Score Oxaliplatinfail to induce cold hypersensitivity and preservemechanical pain symptoms in TRPM8 nullmice ** ** * * WT mice ** ** Vehicle TRPA1 Antagonist (HC030031) NS NS Grooming (s) Grooming (s) Score Score TRPA1 implication in cold hypersensitivity

  12. HCN channels : Xx40 Ivabradine (Procoralan®) Non-specific HCN antagonist Vehicle HCN1 NaCl Vehicle * Acetone test Brush test Ivabradine * * NaCl Oxaliplatin Ivabradine Grooming (s) ** Oxaliplatin ** NS Score Reversion of cold hypersensitivity No effects on mechanicalsensibility

  13. Conclusion CEPHALIC cold and mechanical hypersensitivity induced by oxaliplatin Differencies between cephalic and extracephalic territories at both molecular and pharmacological levels

  14. Perspectives Short term • Impact of oxaliplatin on functional TG neurons? • Ca2+ imaging • Involvement of K2P TREK and TRAAK channels? • Use of other KO mice (TREK2, TREK1-TRAAK) • Cephalic and extracephalic behavioral, molecular & pharmacological consequences of repeated oxaliplatin injections  Long term

  15. Acknowledgements Project realized in association with Institut de génomique fonctionnelle (Montpellier) Anne PIZZOCCARO, Emmanuel BOURINET Inserm U1107 (Clermont Ferrand) Neurobiologie de la douleur trigéminale Amélie DESCHEMEAKER, Radhouane DALLEL Laboratoire de pharmacologie fondamentale et clinique de la douleur Vanessa PEREIRA, Maryse CHALUS, Alain ESCHALIER, Jérôme BUSSEROLLES Thankyou for your attention

  16. Channels expression TRPA1 TRPM8 Vandewauw et al., 2013

  17. Cold water aversion test Resultsat 20°C Vehicle x20 pERK 20 °C Oxaliplatin

  18. HCN Channels Postea et al., 2011

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