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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 treatment on cold-sensing DRG neurons properties measured in vitroTime course of intracellular calcium elevation in the four cold-sensitive neurons showing the variability in temperature thresholds (represented by grey arrows).Histogram of frequency distribution of temperature thresholds for cold-sensitive neurons from vehicle- or oxaliplatin-treated mice (dark and open bars, respectively). Distributions of thresholds from vehicle- or oxaliplatin-treated cold-sensitive neurons are fitted, respectively, with a double or a single Gaussian equation. Mean thresholds (±SEM) of vehicle (filled circle: 24.2 ± 0.7°C) and oxaliplatin (open circle: 27.7 ± 0.7°C) are displayed behind the histogram (p = 0.0004).Effect of oxaliplatin or vehicle on the percentage of cold-sensitive neurons in the total number of DRG cells analysed.
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fig03: Effect of oxaliplatin treatment on cold-sensing DRG neurons properties measured in vitroTime course of intracellular calcium elevation in the four cold-sensitive neurons showing the variability in temperature thresholds (represented by grey arrows).Histogram of frequency distribution of temperature thresholds for cold-sensitive neurons from vehicle- or oxaliplatin-treated mice (dark and open bars, respectively). Distributions of thresholds from vehicle- or oxaliplatin-treated cold-sensitive neurons are fitted, respectively, with a double or a single Gaussian equation. Mean thresholds (±SEM) of vehicle (filled circle: 24.2 ± 0.7°C) and oxaliplatin (open circle: 27.7 ± 0.7°C) are displayed behind the histogram (p = 0.0004).Effect of oxaliplatin or vehicle on the percentage of cold-sensitive neurons in the total number of DRG cells analysed.

Mentions: To investigate the cold sensitivity of dorsal root ganglion (DRG) neurons in culture, we measured fluctuations of intracellular calcium in response to cooling. As previously shown (Madrid et al, 2009; Noel et al, 2009), the thresholds of cold-sensitive DRG neurons varied over a large range (35–15°C) as demonstrated by the simultaneous recordings of four cold-sensitive neurons from vehicle-treated mice (Fig 3A). The frequency distribution of threshold temperatures (Fig 3B) shows that cold-sensitive DRGs from vehicle-treated mice can be separated in two subpopulations with high and low thresholds with a limit between the two groups around 25°C. In contrast, the same analysis with cold-sensitive neurons from oxaliplatin-treated mice shows that the vast majority of neurons responds mainly with a low threshold (between 35 and 25°C). Furthermore, we observed in some of these neurons from oxaliplatin-treated mice, episodes of spontaneous intracellular calcium oscillations even before cooling (not shown). In addition, the proportion of cold-sensitive neurons in the culture is doubled by oxaliplatin (Fig 3C) consistent with a state of hyperexcitability of these nociceptors induced by chemotherapy.


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 treatment on cold-sensing DRG neurons properties measured in vitroTime course of intracellular calcium elevation in the four cold-sensitive neurons showing the variability in temperature thresholds (represented by grey arrows).Histogram of frequency distribution of temperature thresholds for cold-sensitive neurons from vehicle- or oxaliplatin-treated mice (dark and open bars, respectively). Distributions of thresholds from vehicle- or oxaliplatin-treated cold-sensitive neurons are fitted, respectively, with a double or a single Gaussian equation. Mean thresholds (±SEM) of vehicle (filled circle: 24.2 ± 0.7°C) and oxaliplatin (open circle: 27.7 ± 0.7°C) are displayed behind the histogram (p = 0.0004).Effect of oxaliplatin or vehicle on the percentage of cold-sensitive neurons in the total number of DRG cells analysed.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3377073&req=5

fig03: Effect of oxaliplatin treatment on cold-sensing DRG neurons properties measured in vitroTime course of intracellular calcium elevation in the four cold-sensitive neurons showing the variability in temperature thresholds (represented by grey arrows).Histogram of frequency distribution of temperature thresholds for cold-sensitive neurons from vehicle- or oxaliplatin-treated mice (dark and open bars, respectively). Distributions of thresholds from vehicle- or oxaliplatin-treated cold-sensitive neurons are fitted, respectively, with a double or a single Gaussian equation. Mean thresholds (±SEM) of vehicle (filled circle: 24.2 ± 0.7°C) and oxaliplatin (open circle: 27.7 ± 0.7°C) are displayed behind the histogram (p = 0.0004).Effect of oxaliplatin or vehicle on the percentage of cold-sensitive neurons in the total number of DRG cells analysed.
Mentions: To investigate the cold sensitivity of dorsal root ganglion (DRG) neurons in culture, we measured fluctuations of intracellular calcium in response to cooling. As previously shown (Madrid et al, 2009; Noel et al, 2009), the thresholds of cold-sensitive DRG neurons varied over a large range (35–15°C) as demonstrated by the simultaneous recordings of four cold-sensitive neurons from vehicle-treated mice (Fig 3A). The frequency distribution of threshold temperatures (Fig 3B) shows that cold-sensitive DRGs from vehicle-treated mice can be separated in two subpopulations with high and low thresholds with a limit between the two groups around 25°C. In contrast, the same analysis with cold-sensitive neurons from oxaliplatin-treated mice shows that the vast majority of neurons responds mainly with a low threshold (between 35 and 25°C). Furthermore, we observed in some of these neurons from oxaliplatin-treated mice, episodes of spontaneous intracellular calcium oscillations even before cooling (not shown). In addition, the proportion of cold-sensitive neurons in the culture is doubled by oxaliplatin (Fig 3C) consistent with a state of hyperexcitability of these nociceptors induced by chemotherapy.

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