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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 show reduced exploratory activity following each drug treatment cycle. Data represent the mean ± S.EM of 6 mice, **P < 0.01; ***P < 0.001, two-way ANOVA followed with post hoc analysis.
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Figure 2: Cisplatin-treated mice show reduced exploratory activity following each drug treatment cycle. Data represent the mean ± S.EM of 6 mice, **P < 0.01; ***P < 0.001, two-way ANOVA followed with post hoc analysis.

Mentions: At baseline, there was no significant difference observed in the mean locomotor activity or horizontal distance traveled between mice for all groups (Fig. 2, P > 0.05, two-way ANOVA). However, there was a significant decrease in mean distance traveled by mice in the cisplatin group compared to vehicle controls after the first treatment cycle (119.52 ± 15.88 cm vs 319.92 ± 43.89 cm, (*P < 0.05, ANOVA), and after the second treatment cycle (142.30 ± 28.10 cm vs 394.85 ± 61.93 cm, **P < 0.01, ANOVA). A lesser reduction in mean distance traveled was also observed after each treatment cycle in the oxaliplatin group, but the decrease was not statistically significant (P > 0.05, ANOVA). Mice in both drug groups gradually returned to their normal exploratory behaviors and no significant difference was observed in the mean horizontal distance traveled in all groups at weeks six or eight (P > 0.05, ANOVA). These data suggest that the observed increases in responses to painful stimuli in the drug treatment groups are not due to an overall increase in general activity.


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 show reduced exploratory activity following each drug treatment cycle. Data represent the mean ± S.EM of 6 mice, **P < 0.01; ***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 2: Cisplatin-treated mice show reduced exploratory activity following each drug treatment cycle. Data represent the mean ± S.EM of 6 mice, **P < 0.01; ***P < 0.001, two-way ANOVA followed with post hoc analysis.
Mentions: At baseline, there was no significant difference observed in the mean locomotor activity or horizontal distance traveled between mice for all groups (Fig. 2, P > 0.05, two-way ANOVA). However, there was a significant decrease in mean distance traveled by mice in the cisplatin group compared to vehicle controls after the first treatment cycle (119.52 ± 15.88 cm vs 319.92 ± 43.89 cm, (*P < 0.05, ANOVA), and after the second treatment cycle (142.30 ± 28.10 cm vs 394.85 ± 61.93 cm, **P < 0.01, ANOVA). A lesser reduction in mean distance traveled was also observed after each treatment cycle in the oxaliplatin group, but the decrease was not statistically significant (P > 0.05, ANOVA). Mice in both drug groups gradually returned to their normal exploratory behaviors and no significant difference was observed in the mean horizontal distance traveled in all groups at weeks six or eight (P > 0.05, ANOVA). These data suggest that the observed increases in responses to painful stimuli in the drug treatment groups are not due to an overall increase in general activity.

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