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Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli.

Ta LE, Low PA, Windebank AJ - Mol Pain (2009)

Bottom Line: Oxaliplatin induces distinctive cold-associated dysesthesias in up to 80% of patients.In addition, the cisplatin group exhibited significant thermal hyperalgesia in hind paws and tail, and the oxaliplatin group developed significant cold hyperalgesia in hind paws.This model should be useful in studying the molecular basis for these different pain responses and in designing protective therapeutic strategies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Molecular Neuroscience, Mayo Graduate School and Cellular Neurobiology Laboratory, Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA. ta.lauren@mayo.edu

ABSTRACT

Background: Cisplatin has been in use for 40 years for treatment of germ line and other forms of cancer. Oxaliplatin is approved for treatment of metastatic colorectal cancer. Thirty to forty percent of cancer patients receiving these agents develop pain and sensory loss. Oxaliplatin induces distinctive cold-associated dysesthesias in up to 80% of patients.

Results: We have established mouse models of cisplatin and oxaliplatin-induced neuropathy using doses similar to those used in patients. Adult male C57BL6J mice were treated with daily intraperitoneal injection for 5 days, followed by 5 days of rest, for two cycles. Total cumulative doses of 23 mg/kg cisplatin and 30 mg/kg oxaliplatin were used. Behavioral evaluations included cold plate, von Frey, radiant heat, tail immersion, grip strength and exploratory behavior at baseline and at weekly intervals for 8 weeks. Following two treatment cycles, mice in the cisplatin and oxaliplatin treatment groups demonstrated significant mechanical allodynia compared to control mice. In addition, the cisplatin group exhibited significant thermal hyperalgesia in hind paws and tail, and the oxaliplatin group developed significant cold hyperalgesia in hind paws.

Conclusion: We have therefore established a model of platinum drug-induced painful peripheral neuropathy that reflects the differences in early thermal pain responses that are observed in patients treated with either cisplatin or oxaliplatin. This model should be useful in studying the molecular basis for these different pain responses and in designing protective therapeutic strategies.

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Cisplatin-treated mice have reduced body weight after each drug treatment cycle. Data represent the mean ± S.EM of 7 mice, *P < 0.05; ***P < 0.001, two-way ANOVA followed with post hoc analysis.
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Figure 1: Cisplatin-treated mice have reduced body weight after each drug treatment cycle. Data represent the mean ± S.EM of 7 mice, *P < 0.05; ***P < 0.001, two-way ANOVA followed with post hoc analysis.

Mentions: All mice maintained grooming habits, had normal skin texture on all paws and tail, and exhibited no signs of autotomy. No significant difference of body weight was observed at base line between mice in the three groups (Fig. 1, P > 0.05, two-way ANOVA). However, there was a significant decrease in mean body weight in the cisplatin group compared to vehicle control after the first treatment cycle (23.62 ± 0.73 g vs 26.66 ± 0. 49 g, (*P < 0.05, ANOVA); and after the second treatment cycle (22.76 ± 0.91 g vs 27.43 ± 0. 50 g, ***P < 0.001, ANOVA). While a similar trend of weight reduction was seen in the oxaliplatin group after each treatment cycle, this difference was not statistically significant compared to the controls (P > 0.05, ANOVA). Mice in both drug groups gradually regained body weight and no significant difference in mean body weight was present between groups after six and eight weeks (Fig. 1, P > 0.05, ANOVA).


Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli.

Ta LE, Low PA, Windebank AJ - Mol Pain (2009)

Cisplatin-treated mice have reduced body weight after each drug treatment cycle. Data represent the mean ± S.EM of 7 mice, *P < 0.05; ***P < 0.001, two-way ANOVA followed with post hoc analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2655284&req=5

Figure 1: Cisplatin-treated mice have reduced body weight after each drug treatment cycle. Data represent the mean ± S.EM of 7 mice, *P < 0.05; ***P < 0.001, two-way ANOVA followed with post hoc analysis.
Mentions: All mice maintained grooming habits, had normal skin texture on all paws and tail, and exhibited no signs of autotomy. No significant difference of body weight was observed at base line between mice in the three groups (Fig. 1, P > 0.05, two-way ANOVA). However, there was a significant decrease in mean body weight in the cisplatin group compared to vehicle control after the first treatment cycle (23.62 ± 0.73 g vs 26.66 ± 0. 49 g, (*P < 0.05, ANOVA); and after the second treatment cycle (22.76 ± 0.91 g vs 27.43 ± 0. 50 g, ***P < 0.001, ANOVA). While a similar trend of weight reduction was seen in the oxaliplatin group after each treatment cycle, this difference was not statistically significant compared to the controls (P > 0.05, ANOVA). Mice in both drug groups gradually regained body weight and no significant difference in mean body weight was present between groups after six and eight weeks (Fig. 1, P > 0.05, ANOVA).

Bottom Line: Oxaliplatin induces distinctive cold-associated dysesthesias in up to 80% of patients.In addition, the cisplatin group exhibited significant thermal hyperalgesia in hind paws and tail, and the oxaliplatin group developed significant cold hyperalgesia in hind paws.This model should be useful in studying the molecular basis for these different pain responses and in designing protective therapeutic strategies.

View Article: PubMed Central - HTML - PubMed

Affiliation: Program in Molecular Neuroscience, Mayo Graduate School and Cellular Neurobiology Laboratory, Department of Neurology, Mayo Clinic, College of Medicine, Rochester, MN 55905, USA. ta.lauren@mayo.edu

ABSTRACT

Background: Cisplatin has been in use for 40 years for treatment of germ line and other forms of cancer. Oxaliplatin is approved for treatment of metastatic colorectal cancer. Thirty to forty percent of cancer patients receiving these agents develop pain and sensory loss. Oxaliplatin induces distinctive cold-associated dysesthesias in up to 80% of patients.

Results: We have established mouse models of cisplatin and oxaliplatin-induced neuropathy using doses similar to those used in patients. Adult male C57BL6J mice were treated with daily intraperitoneal injection for 5 days, followed by 5 days of rest, for two cycles. Total cumulative doses of 23 mg/kg cisplatin and 30 mg/kg oxaliplatin were used. Behavioral evaluations included cold plate, von Frey, radiant heat, tail immersion, grip strength and exploratory behavior at baseline and at weekly intervals for 8 weeks. Following two treatment cycles, mice in the cisplatin and oxaliplatin treatment groups demonstrated significant mechanical allodynia compared to control mice. In addition, the cisplatin group exhibited significant thermal hyperalgesia in hind paws and tail, and the oxaliplatin group developed significant cold hyperalgesia in hind paws.

Conclusion: We have therefore established a model of platinum drug-induced painful peripheral neuropathy that reflects the differences in early thermal pain responses that are observed in patients treated with either cisplatin or oxaliplatin. This model should be useful in studying the molecular basis for these different pain responses and in designing protective therapeutic strategies.

Show MeSH
Related in: MedlinePlus