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

Descoeur J, Pereira V, Pizzoccaro A, Francois A, Ling B, Maffre V, Couette B, Busserolles J, Courteix C, Noel J, Lazdunski M, Eschalier A, Authier N, Bourinet E - EMBO Mol Med (2011)

Bottom Line: To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed.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).

View Article: PubMed Central - PubMed

Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.

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Related in: MedlinePlus

Effect of oxaliplatin (6 mg/kg) on TREK1-TRAAK KO miceDynamic cold plate test performed before (filled circles, n = 10) and 90 h after oxaliplatin injection (open circles, n = 10). Nocifensive reactions were measured from 22 to 1°C.Thermal place preference before (filled bars) and 90 h after oxaliplatin injection (open bars, n = 10). Mice were allowed to choose between adjacent surfaces adjusted to 25°C versus 23°C or 21°C.Effect of oxaliplatin on mechanical perception on the same TREK1-TRAAK KO mice as in (A) and (B) (n = 10 per group). Numbers of paw lifts out of five mechanical stimulations using a von Frey filament of 1.4 g bending force.
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fig07: Effect of oxaliplatin (6 mg/kg) on TREK1-TRAAK KO miceDynamic cold plate test performed before (filled circles, n = 10) and 90 h after oxaliplatin injection (open circles, n = 10). Nocifensive reactions were measured from 22 to 1°C.Thermal place preference before (filled bars) and 90 h after oxaliplatin injection (open bars, n = 10). Mice were allowed to choose between adjacent surfaces adjusted to 25°C versus 23°C or 21°C.Effect of oxaliplatin on mechanical perception on the same TREK1-TRAAK KO mice as in (A) and (B) (n = 10 per group). Numbers of paw lifts out of five mechanical stimulations using a von Frey filament of 1.4 g bending force.

Mentions: One of the most marked transcript expression changes observed was a decrease in background potassium channels. Consequently, we asked whether oxaliplatin-induced cold hypersensitivity would still develop in mice invalidated for both TREK1 and TRAAK subunits. As presented in Fig 7A and B, vehicle-treated TREK1-TRAAK KO animals presented a tonic intolerance to noxious cold (Fig 7A) and cool allodynia (Fig 7B) similar to that of wild type animals after oxaliplatin treatment (Fig 1B and D). Interestingly, oxaliplatin failed to increase this tonic hypersensitivity to cold in the double KO mice, demonstrating a total loss of oxaliplatin modulation of cold perception in this genotype in agreement with the qPCR results. As previously described, the TREK1-TRAAK KO mice presented a robust mechanical hyperalgesia that could not be further modified by oxaliplatin (Fig 7C).


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

Descoeur J, Pereira V, Pizzoccaro A, Francois A, Ling B, Maffre V, Couette B, Busserolles J, Courteix C, Noel J, Lazdunski M, Eschalier A, Authier N, Bourinet E - EMBO Mol Med (2011)

Effect of oxaliplatin (6 mg/kg) on TREK1-TRAAK KO miceDynamic cold plate test performed before (filled circles, n = 10) and 90 h after oxaliplatin injection (open circles, n = 10). Nocifensive reactions were measured from 22 to 1°C.Thermal place preference before (filled bars) and 90 h after oxaliplatin injection (open bars, n = 10). Mice were allowed to choose between adjacent surfaces adjusted to 25°C versus 23°C or 21°C.Effect of oxaliplatin on mechanical perception on the same TREK1-TRAAK KO mice as in (A) and (B) (n = 10 per group). Numbers of paw lifts out of five mechanical stimulations using a von Frey filament of 1.4 g bending force.
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Related In: Results  -  Collection

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fig07: Effect of oxaliplatin (6 mg/kg) on TREK1-TRAAK KO miceDynamic cold plate test performed before (filled circles, n = 10) and 90 h after oxaliplatin injection (open circles, n = 10). Nocifensive reactions were measured from 22 to 1°C.Thermal place preference before (filled bars) and 90 h after oxaliplatin injection (open bars, n = 10). Mice were allowed to choose between adjacent surfaces adjusted to 25°C versus 23°C or 21°C.Effect of oxaliplatin on mechanical perception on the same TREK1-TRAAK KO mice as in (A) and (B) (n = 10 per group). Numbers of paw lifts out of five mechanical stimulations using a von Frey filament of 1.4 g bending force.
Mentions: One of the most marked transcript expression changes observed was a decrease in background potassium channels. Consequently, we asked whether oxaliplatin-induced cold hypersensitivity would still develop in mice invalidated for both TREK1 and TRAAK subunits. As presented in Fig 7A and B, vehicle-treated TREK1-TRAAK KO animals presented a tonic intolerance to noxious cold (Fig 7A) and cool allodynia (Fig 7B) similar to that of wild type animals after oxaliplatin treatment (Fig 1B and D). Interestingly, oxaliplatin failed to increase this tonic hypersensitivity to cold in the double KO mice, demonstrating a total loss of oxaliplatin modulation of cold perception in this genotype in agreement with the qPCR results. As previously described, the TREK1-TRAAK KO mice presented a robust mechanical hyperalgesia that could not be further modified by oxaliplatin (Fig 7C).

Bottom Line: To date, pain management strategies have failed to alleviate these symptoms, hence development of adapted analgesics is needed.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).

View Article: PubMed Central - PubMed

Affiliation: Département de Physiologie, CNRS, UMR-5203, Institut de Génomique Fonctionnelle, Montpellier, France.

Show MeSH
Related in: MedlinePlus