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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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Laura poupon 1 re ann e de th se 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, 1ère année de thèse

U1107 – Pharmacologie fondamentale et clinique de la douleur

Directeur : Pr. A. Eschalier


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

Existingextracephalicresults in mice

Clinical symptoms

Mice model

Cold hyperalgesia

DRG

Mechanical hypersensitivity

Descoeur et al., 2011


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

Differencesbetweencephalic and extracephalic sensorysystems

Sensory systems

Extracephalic

Cephalic

TG

DRG

A-fibers

C-fibers

Caudalis

?


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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 ?

?


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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)


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

Ion channels plasticity in DRG and TG

qPCR

Extracephalic (DRG)

Vehicle

Oxaliplatin

Cephalic (TG)


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

Conclusion

CEPHALIC cold and mechanical hypersensitivity induced by oxaliplatin

Differencies between cephalic and extracephalic territories at both molecular and pharmacological levels


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

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


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

Channels expression

TRPA1

TRPM8

Vandewauw et al., 2013


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

Cold water aversion test

Resultsat 20°C

Vehicle x20

pERK

20 °C

Oxaliplatin


Laura poupon 1 re ann e de th se u1107 pharmacologie fondamentale et clinique de la douleur

HCN Channels

Postea et al., 2011


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