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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 exhibit thermal hyperalgesia to radiant heat assay. Cisplatin-treated mice show decreased response withdrawal latencies to noxious thermal stimuli at weeks 3, 6, and 8. 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 5: Cisplatin-treated mice exhibit thermal hyperalgesia to radiant heat assay. Cisplatin-treated mice show decreased response withdrawal latencies to noxious thermal stimuli at weeks 3, 6, and 8. Data represent the mean ± S.EM of 7 mice, *P < 0.05; ***P < 0.001, two-way ANOVA followed with post hoc analysis.

Mentions: Clear and robust heat evoked responses were observed in two behavioral heat assays (radiant heat and tail immersion) from cisplatin-treated mice demonstrating that cisplatin induces thermal hyperalgesia in this model. In contrast, no such heat responses were observed for oxaliplatin-treated mice. Cisplatin induced significant thermal nociception to hind paw (Fig. 5), which paralleled with the mechanical nociception as previously observed in Von Frey assay (Fig. 4). At baseline, there was no significant difference between groups in paw withdrawal responses to noxious heat stimuli (Fig. 5, P > 0.05, two-way ANOVA). After two cycles of drug treatment, the cisplatin group developed a significant 37% decrease in paw withdrawal latencies compared to the vehicle group (4.29 ± 0.36 s vs 6.85 ± 0. 0.36 s, ***P < 0.001, two-way ANOVA). The cisplatin group continued to exhibit significant 30% and 18% decreases in paw withdrawal latencies compared to the vehicle group at weeks six and eight, respectively (***P < 0.001 and *P < 0.05, two-way ANOVA). Although there was a decrease in paw withdrawal latency in the oxaliplatin group compared to the vehicle group, the difference was not significant after 3, 6 or 8 weeks (P > 0.05, two-way 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 exhibit thermal hyperalgesia to radiant heat assay. Cisplatin-treated mice show decreased response withdrawal latencies to noxious thermal stimuli at weeks 3, 6, and 8. 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 5: Cisplatin-treated mice exhibit thermal hyperalgesia to radiant heat assay. Cisplatin-treated mice show decreased response withdrawal latencies to noxious thermal stimuli at weeks 3, 6, and 8. Data represent the mean ± S.EM of 7 mice, *P < 0.05; ***P < 0.001, two-way ANOVA followed with post hoc analysis.
Mentions: Clear and robust heat evoked responses were observed in two behavioral heat assays (radiant heat and tail immersion) from cisplatin-treated mice demonstrating that cisplatin induces thermal hyperalgesia in this model. In contrast, no such heat responses were observed for oxaliplatin-treated mice. Cisplatin induced significant thermal nociception to hind paw (Fig. 5), which paralleled with the mechanical nociception as previously observed in Von Frey assay (Fig. 4). At baseline, there was no significant difference between groups in paw withdrawal responses to noxious heat stimuli (Fig. 5, P > 0.05, two-way ANOVA). After two cycles of drug treatment, the cisplatin group developed a significant 37% decrease in paw withdrawal latencies compared to the vehicle group (4.29 ± 0.36 s vs 6.85 ± 0. 0.36 s, ***P < 0.001, two-way ANOVA). The cisplatin group continued to exhibit significant 30% and 18% decreases in paw withdrawal latencies compared to the vehicle group at weeks six and eight, respectively (***P < 0.001 and *P < 0.05, two-way ANOVA). Although there was a decrease in paw withdrawal latency in the oxaliplatin group compared to the vehicle group, the difference was not significant after 3, 6 or 8 weeks (P > 0.05, two-way 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