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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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Effect of oxaliplatin (6 mg/kg) on TRMP8 KO miceDynamic cold plate test performed before (filled circles) and 90 h after oxaliplatin injection (open circles, n = 10). Nocifensive reactions were measured from 22 to 1°C. Grey dotted lines represent the reactions of vehicle- and oxaliplatin-treated wild type mice.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 TRPM8 KO mice as in (A) and (B) (n = 10 per group). Numbers of paw lifts out of 5 mechanical stimulations using a von Frey filament of 1.4 g bending force.
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fig04: Effect of oxaliplatin (6 mg/kg) on TRMP8 KO miceDynamic cold plate test performed before (filled circles) and 90 h after oxaliplatin injection (open circles, n = 10). Nocifensive reactions were measured from 22 to 1°C. Grey dotted lines represent the reactions of vehicle- and oxaliplatin-treated wild type mice.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 TRPM8 KO mice as in (A) and (B) (n = 10 per group). Numbers of paw lifts out of 5 mechanical stimulations using a von Frey filament of 1.4 g bending force.

Mentions: Pharmacological characterization of cold-sensitive neurons in vitro using chemical agonists showed that these cells from both vehicle- and oxaliplatin-treated mice similarly use TRPM8 as the major cold transduction mechanism (Supporting Fig 2). Moreover, cool allodynia develops in the range of temperatures activating the thermoreceptor TRPM8 (McKemy et al, 2002; Peier et al, 2002). Thus, we evaluated whether the effects of oxaliplatin would be abolished in mice deficient for this channel. As presented in Fig 4A, in the cold tolerance paradigm used, TRPM8- mice did not elicit nocifencive behaviour to noxious cold either before or 90 h after oxaliplatin injection. Similarly, in the thermal preference test (Fig 4B), oxaliplatin failed to induce cool allodynia in TRMP8 nice in contrast to wild type animals (Fig 1D). However, the mechanical pain symptoms still developed in these knock out (KO) mice (Fig 4C). Collectively, these results indicate that oxaliplatin mediates a cold hypersensitivity (both hyperalgesia to noxious cold, and allodynia to innocuous cool) via TRPM8 afferent fibres, but the mechanism remains to be determined.


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 TRMP8 KO miceDynamic cold plate test performed before (filled circles) and 90 h after oxaliplatin injection (open circles, n = 10). Nocifensive reactions were measured from 22 to 1°C. Grey dotted lines represent the reactions of vehicle- and oxaliplatin-treated wild type mice.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 TRPM8 KO mice as in (A) and (B) (n = 10 per group). Numbers of paw lifts out of 5 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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fig04: Effect of oxaliplatin (6 mg/kg) on TRMP8 KO miceDynamic cold plate test performed before (filled circles) and 90 h after oxaliplatin injection (open circles, n = 10). Nocifensive reactions were measured from 22 to 1°C. Grey dotted lines represent the reactions of vehicle- and oxaliplatin-treated wild type mice.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 TRPM8 KO mice as in (A) and (B) (n = 10 per group). Numbers of paw lifts out of 5 mechanical stimulations using a von Frey filament of 1.4 g bending force.
Mentions: Pharmacological characterization of cold-sensitive neurons in vitro using chemical agonists showed that these cells from both vehicle- and oxaliplatin-treated mice similarly use TRPM8 as the major cold transduction mechanism (Supporting Fig 2). Moreover, cool allodynia develops in the range of temperatures activating the thermoreceptor TRPM8 (McKemy et al, 2002; Peier et al, 2002). Thus, we evaluated whether the effects of oxaliplatin would be abolished in mice deficient for this channel. As presented in Fig 4A, in the cold tolerance paradigm used, TRPM8- mice did not elicit nocifencive behaviour to noxious cold either before or 90 h after oxaliplatin injection. Similarly, in the thermal preference test (Fig 4B), oxaliplatin failed to induce cool allodynia in TRMP8 nice in contrast to wild type animals (Fig 1D). However, the mechanical pain symptoms still developed in these knock out (KO) mice (Fig 4C). Collectively, these results indicate that oxaliplatin mediates a cold hypersensitivity (both hyperalgesia to noxious cold, and allodynia to innocuous cool) via TRPM8 afferent fibres, but the mechanism remains to be determined.

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