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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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Oxaliplatin effects on cold/cool perception of miceWithdrawal thresholds to tail immersion at 10°C measured daily for 6 days before treatment (day 0) and after single i.p. injection with vehicle (filled circles, n = 10) or 1, 3 or 6 mg/kg of oxaliplatin (open triangle, open square and open circle, respectively; n = 10 per group). The dotted line at 15 s represents the test cut off value.Dynamic cold plate test performed 90 h after vehicle/oxaliplatin injection. The number of nocifensive reactions (jumps) was measured from 30 to 1°C (vehicle: filled circles; oxaliplatin 6 mg/kg open circles; n = 8 per group).Withdrawal thresholds to tail immersion at 21°C measured daily for 6 days in mice before (day 0) and after single i.p. injection with vehicle (filled circles, n = 10) or 1, 3 or 6 mg/kg of oxaliplatin (open triangle, open square and open circle, respectively; n = 10 per group).Thermic place preference at 90 h post vehicle/oxaliplatin injection. Mice were allowed to choose between adjacent surfaces set to 25°C versus a range of temperatures as shown. The percentage of time spent at 25°C over a 3 min period is shown. Filled and open bars represent the vehicle and the oxaliplatin (6 mg/kg) groups, respectively (n = 10 mice per group).
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fig01: Oxaliplatin effects on cold/cool perception of miceWithdrawal thresholds to tail immersion at 10°C measured daily for 6 days before treatment (day 0) and after single i.p. injection with vehicle (filled circles, n = 10) or 1, 3 or 6 mg/kg of oxaliplatin (open triangle, open square and open circle, respectively; n = 10 per group). The dotted line at 15 s represents the test cut off value.Dynamic cold plate test performed 90 h after vehicle/oxaliplatin injection. The number of nocifensive reactions (jumps) was measured from 30 to 1°C (vehicle: filled circles; oxaliplatin 6 mg/kg open circles; n = 8 per group).Withdrawal thresholds to tail immersion at 21°C measured daily for 6 days in mice before (day 0) and after single i.p. injection with vehicle (filled circles, n = 10) or 1, 3 or 6 mg/kg of oxaliplatin (open triangle, open square and open circle, respectively; n = 10 per group).Thermic place preference at 90 h post vehicle/oxaliplatin injection. Mice were allowed to choose between adjacent surfaces set to 25°C versus a range of temperatures as shown. The percentage of time spent at 25°C over a 3 min period is shown. Filled and open bars represent the vehicle and the oxaliplatin (6 mg/kg) groups, respectively (n = 10 mice per group).

Mentions: To assess cold sensitivity in mice, we first measured acute tail withdrawal response to a noxious cold stimulation (Fig 1A). Vehicle-treated mice showed stable thresholds through the duration of the experiments (one daily test for 1 week). In contrast, oxaliplatin-treated animals exhibited altered cold sensitivity. Oxaliplatin induced a clear dose-dependent and transient reduction of withdrawal thresholds that peaked 90 h post injection and reversed towards control values thereafter (Fig 1A). At 6 mg/kg (therapeutic dose), the cold hypersensitivity was manifested by a 50% threshold decrease. The tail immersion test is mainly supported by a spinal reflex arc, thus, in order to have a more integrated behaviour, we challenged the mice on a dynamic cold plate (Yalcin et al, 2009). This test entails the slow lowering of temperature of the test arena floor from warm to cold and quantifying spontaneous nocifencive behaviour to ascertain the tolerance threshold to noxious cold. Vehicle-treated animals manifested escape behaviour at approximately 5°C, whilst oxaliplatin-treated mice presented the same escape behaviour at a much more elevated temperature (∼15°C), reflecting a clear cold hypersensitivity (Fig 1B). To discriminate allodynic effects, we performed the tail immersion test at an innocuous temperature (21°C). This temperature does not elicit any withdrawal in vehicle-treated animals, whilst it induced withdrawals in oxaliplatin-treated mice, with the same dose dependency as for cold hyperalgesia (Fig 1C). Spontaneous allodynia was assessed in these animals through their ability to discriminate between warm and cool surfaces. Mice were allowed to explore adjacent surfaces, with one held at 25°C and the other ranging from 25 to 15°C, a temperature range considered to be innocuously cool (Rainville et al, 1999) (Fig 1D). When both sides were at the same temperature (both 25°C), neither vehicle- nor oxaliplatin-treated mice displayed any preference. As the variable plate was cooled, vehicle-treated mice started to show a preference for the warm side when the variable side was below 19°C. With oxaliplatin treatment, the preference of the mice for the warm side developed as soon as the variable side was set to 23°C, demonstrating clear allodynic behaviour to cool temperatures (Fig 1D). In parallel, we assessed sensitivity of the mice to noxious heat through their response to tail immersion at 46°C (Supporting Fig 1A). Vehicle- or oxaliplatin-treated mice at all doses showed indistinguishable thresholds during the entire duration of the experiments (one daily test for 1 week), reflecting an unaltered response to heat.


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)

Oxaliplatin effects on cold/cool perception of miceWithdrawal thresholds to tail immersion at 10°C measured daily for 6 days before treatment (day 0) and after single i.p. injection with vehicle (filled circles, n = 10) or 1, 3 or 6 mg/kg of oxaliplatin (open triangle, open square and open circle, respectively; n = 10 per group). The dotted line at 15 s represents the test cut off value.Dynamic cold plate test performed 90 h after vehicle/oxaliplatin injection. The number of nocifensive reactions (jumps) was measured from 30 to 1°C (vehicle: filled circles; oxaliplatin 6 mg/kg open circles; n = 8 per group).Withdrawal thresholds to tail immersion at 21°C measured daily for 6 days in mice before (day 0) and after single i.p. injection with vehicle (filled circles, n = 10) or 1, 3 or 6 mg/kg of oxaliplatin (open triangle, open square and open circle, respectively; n = 10 per group).Thermic place preference at 90 h post vehicle/oxaliplatin injection. Mice were allowed to choose between adjacent surfaces set to 25°C versus a range of temperatures as shown. The percentage of time spent at 25°C over a 3 min period is shown. Filled and open bars represent the vehicle and the oxaliplatin (6 mg/kg) groups, respectively (n = 10 mice per group).
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fig01: Oxaliplatin effects on cold/cool perception of miceWithdrawal thresholds to tail immersion at 10°C measured daily for 6 days before treatment (day 0) and after single i.p. injection with vehicle (filled circles, n = 10) or 1, 3 or 6 mg/kg of oxaliplatin (open triangle, open square and open circle, respectively; n = 10 per group). The dotted line at 15 s represents the test cut off value.Dynamic cold plate test performed 90 h after vehicle/oxaliplatin injection. The number of nocifensive reactions (jumps) was measured from 30 to 1°C (vehicle: filled circles; oxaliplatin 6 mg/kg open circles; n = 8 per group).Withdrawal thresholds to tail immersion at 21°C measured daily for 6 days in mice before (day 0) and after single i.p. injection with vehicle (filled circles, n = 10) or 1, 3 or 6 mg/kg of oxaliplatin (open triangle, open square and open circle, respectively; n = 10 per group).Thermic place preference at 90 h post vehicle/oxaliplatin injection. Mice were allowed to choose between adjacent surfaces set to 25°C versus a range of temperatures as shown. The percentage of time spent at 25°C over a 3 min period is shown. Filled and open bars represent the vehicle and the oxaliplatin (6 mg/kg) groups, respectively (n = 10 mice per group).
Mentions: To assess cold sensitivity in mice, we first measured acute tail withdrawal response to a noxious cold stimulation (Fig 1A). Vehicle-treated mice showed stable thresholds through the duration of the experiments (one daily test for 1 week). In contrast, oxaliplatin-treated animals exhibited altered cold sensitivity. Oxaliplatin induced a clear dose-dependent and transient reduction of withdrawal thresholds that peaked 90 h post injection and reversed towards control values thereafter (Fig 1A). At 6 mg/kg (therapeutic dose), the cold hypersensitivity was manifested by a 50% threshold decrease. The tail immersion test is mainly supported by a spinal reflex arc, thus, in order to have a more integrated behaviour, we challenged the mice on a dynamic cold plate (Yalcin et al, 2009). This test entails the slow lowering of temperature of the test arena floor from warm to cold and quantifying spontaneous nocifencive behaviour to ascertain the tolerance threshold to noxious cold. Vehicle-treated animals manifested escape behaviour at approximately 5°C, whilst oxaliplatin-treated mice presented the same escape behaviour at a much more elevated temperature (∼15°C), reflecting a clear cold hypersensitivity (Fig 1B). To discriminate allodynic effects, we performed the tail immersion test at an innocuous temperature (21°C). This temperature does not elicit any withdrawal in vehicle-treated animals, whilst it induced withdrawals in oxaliplatin-treated mice, with the same dose dependency as for cold hyperalgesia (Fig 1C). Spontaneous allodynia was assessed in these animals through their ability to discriminate between warm and cool surfaces. Mice were allowed to explore adjacent surfaces, with one held at 25°C and the other ranging from 25 to 15°C, a temperature range considered to be innocuously cool (Rainville et al, 1999) (Fig 1D). When both sides were at the same temperature (both 25°C), neither vehicle- nor oxaliplatin-treated mice displayed any preference. As the variable plate was cooled, vehicle-treated mice started to show a preference for the warm side when the variable side was below 19°C. With oxaliplatin treatment, the preference of the mice for the warm side developed as soon as the variable side was set to 23°C, demonstrating clear allodynic behaviour to cool temperatures (Fig 1D). In parallel, we assessed sensitivity of the mice to noxious heat through their response to tail immersion at 46°C (Supporting Fig 1A). Vehicle- or oxaliplatin-treated mice at all doses showed indistinguishable thresholds during the entire duration of the experiments (one daily test for 1 week), reflecting an unaltered response to heat.

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