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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 - PowerPoint PPT Presentation
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Molecular and behavioral exploration of orofacial hypersensitivity in a model of oxaliplatin-chemotherapy
induced acute neuropathy
Laura POUPON, 1ère année de thèseU1107 – Pharmacologie fondamentale et clinique de la douleur
Directeur : Pr. A. Eschalier
9ème Symposium National du Réseau Recherche sur la Douleur22 et 23 mars 2013
Oxaliplatin chemotherapy-induced neuropathy
Therapeutic effects
Adverse effects
Used in colorectal cancer chemotherapy
Inhibits DNA replication by platinum adduct formation
90% of patients develop acute neuropathy
Cold hypersensitivity
Numbness at both extracephalic and cephalic territories
Dose reduction to limit neuropathic symptoms
Cephalic territory
Extracephalic territory
Oxaliplatin (Eloxatin®)
Platinum-based antineoplasic
DRG
Cold hyperalgesia
Mechanical hypersensitivity
Existing extracephalic results in mice
Mice modelClinical symptoms
Descoeur et al., 2011
Mice ion channels transcriptional expression
Existing extracephalic results in mice
DRG
Descoeur et al., 2011
Correlation between oxaliplatin-induced cold hypersensitivity and remodelling of ion channel expression in nociceptors
Clinical symptoms
DRG
Differences between cephalic and extracephalic sensory systems
TG
C-fibers
Sensory systems
A-fibers
Caudalis
Cephalic
?
DRG
Extracephalic
Aim of the study
• Development of adapted orofacial behavioral tests
• Assessment of ion channel transcriptional plasticity at the TG level
• Genetic or pharmacological validation of ion channels as targets of interest ?
Are there behavioral and molecular differences between the cephalic and the extracephalic territories in a murine model of oxaliplatin chemotherapy-induced neuropathy
?
Material & Methods
Mice model
Single i.p. injection of oxaliplatin (6mg/kg)
Peak pain behavior at D4
Daily measures of pain scores from D0 to D4
Day
D0 D1 D2 D3 D4
Behavioral tests
Caudalis -TG
HIC(pERK)
qPCR(ion channels)
Oral cold perception in WT mice
J-3 J0 J1 J2 J3 J40
1
2
3
4
5
* *
Wat
er c
onsu
mpti
on (m
L)
Oxaliplatin
Vehicle pERK
Cold water aversion test
Vehicle Oxaliplatin 6 mg/kg
Oral cold Hypersensitivity
D4 - Caudalis
D0 D1 D2 D3 D4
3h3h 3h 3h 3h 3h
4 - 6°C
30 min0
50
100
150
200
250VehOxa
Cutaneous cold and Mechanical perception in WT mice
Scor
e
Vehicle Oxaliplatin 6 mg/kg
J-3 J0 J1 J2 J3 J40
1
2
3
4
*****
Brush test
Response to dynamic mechanical stimulation
5 consecutive strokes
Groo
min
g (s
) ****
J-3 J0 J1 J2 J3 J412
14
16
18Vehicle Oxaliplatin 6 mg/kg
Acetone test
Daily measure of grooming behavior
On the upper lip area skin surface
Cutaneous cold Hypersensitivity Mechanical hypersensitivity
Ion channels plasticity in DRG and TGqPCR
Extracephalic (DRG)
Cephalic (TG)
Vehicle Oxaliplatin
Cold sensors : TRPM8 and TRPA1
J0 J40
4
8
12
16
Groo
min
g (s
)
Scor
e
NSNS
J0 J40
1
2
3
4
****
Vehicle Oxaliplatin 6 mg/kg
TRPM8 -/- mice
Oxaliplatin fail to induce cold hypersensitivity andpreserve mechanical pain symptoms in TRPM8 null mice
Vehicle TRPA1 Antagonist(HC030031)
Groo
min
g (s
)
TRPA1 implication in cold hypersensitivity
WT mice
Scor
e
**NS
qPCR Acetone test Brush test
J0 J41
5
9
13
J0 J40
1
2
3
4
*****
NS
***
Groo
min
g (s
)
Scor
e
HCN channels :
J0 J40
1
2
3
4
5 ****
Scor
e
NSNaClIvabradine NaClIvabradine
Vehicle
Oxaliplatin
Acetone test Brush test
Groo
min
g (s
)
J0 J412
14
16
18 * **
Ivabradine (Procoralan®)
Non-specific HCN antagonist
Reversion of cold hypersensitivityNo effects on mechanical sensibility
Oxaliplatin
Vehicle HCN1
Xx40
Conclusion
CEPHALIC cold and mechanical hypersensitivity induced by oxaliplatin
Differencies between cephalic and extracephalic territories at both molecular and pharmacological levels
Extracephalic (DRG) Cephalic (TG)
TRPM8 → + - → + -
TRPA1 ↗ - + → + -HCN1 - HCN2 ↗ + - ↗↗ + -
Perspectives
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
Short term
Long term
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 DALLELLaboratoire de pharmacologie fondamentale et clinique de la douleur
Vanessa PEREIRA, Maryse CHALUS, Alain ESCHALIER, Jérôme BUSSEROLLES
Thank you for your attention
Vandewauw et al., 2013
Channels expression
TRPA
1
TRPM
8
Cold water aversion test
Results at 20°C
20 °C
Vehicle x20
Oxaliplatin
pERK
HCN Channels
Postea et al., 2011
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