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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 developed thermal hyperagesia to tail immersion assay. Cisplatin-treated mice show decreased response tail flick latencies to noxious thermal stimuli at weeks 4 and 6. 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 6: Cisplatin-treated mice developed thermal hyperagesia to tail immersion assay. Cisplatin-treated mice show decreased response tail flick latencies to noxious thermal stimuli at weeks 4 and 6. Data represent the mean ± S.EM of 7 mice, *P < 0.05; ***P < 0.001, two-way ANOVA followed with post hoc analysis.

Mentions: In the tail immersion assay, there was no significant difference in response to noxious heat stimuli between treatment groups at baseline (Fig. 6, P > 0.05, ANOVA). However, after two cycles of drug administration, the cisplatin group exhibited highly significant thermal hyperalgesia compared to the vehicle group, and this heat hypersensitivity persisted with a 46% decrease in tail flick latency at week four (1.83 ± 0.23 s vs 3.39 ± 0.19 s, ***P < 0.05, ANOVA), and a 36% decrease in tail flick latency at week six (2.15 ± 0.14 s vs 3.36 ± 0.33 s, *P < 0.05, ANOVA). The lower level of thermal hyperalgesia starting at week 8 depicted the gradual return to baseline of heat response for both paws (Fig. 5) and tail (Fig. 6) in cisplatin treated mice, which indicated the threshold cisplatin dose used in our study. This recovery of responsiveness to heat stimuli may be unlikely to occur with repeated cisplatin administration or higher accumulative doses. Similar observations were found in rats which were given a range of low to high doses of cisplatin [33]. A different pattern of heat evoked response was observed with oxaliplatin. Although there was a decrease in tail flick latency in the oxaliplatin group compared to the vehicle group, the difference was not significant at weeks six and eight (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 developed thermal hyperagesia to tail immersion assay. Cisplatin-treated mice show decreased response tail flick latencies to noxious thermal stimuli at weeks 4 and 6. 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 6: Cisplatin-treated mice developed thermal hyperagesia to tail immersion assay. Cisplatin-treated mice show decreased response tail flick latencies to noxious thermal stimuli at weeks 4 and 6. Data represent the mean ± S.EM of 7 mice, *P < 0.05; ***P < 0.001, two-way ANOVA followed with post hoc analysis.
Mentions: In the tail immersion assay, there was no significant difference in response to noxious heat stimuli between treatment groups at baseline (Fig. 6, P > 0.05, ANOVA). However, after two cycles of drug administration, the cisplatin group exhibited highly significant thermal hyperalgesia compared to the vehicle group, and this heat hypersensitivity persisted with a 46% decrease in tail flick latency at week four (1.83 ± 0.23 s vs 3.39 ± 0.19 s, ***P < 0.05, ANOVA), and a 36% decrease in tail flick latency at week six (2.15 ± 0.14 s vs 3.36 ± 0.33 s, *P < 0.05, ANOVA). The lower level of thermal hyperalgesia starting at week 8 depicted the gradual return to baseline of heat response for both paws (Fig. 5) and tail (Fig. 6) in cisplatin treated mice, which indicated the threshold cisplatin dose used in our study. This recovery of responsiveness to heat stimuli may be unlikely to occur with repeated cisplatin administration or higher accumulative doses. Similar observations were found in rats which were given a range of low to high doses of cisplatin [33]. A different pattern of heat evoked response was observed with oxaliplatin. Although there was a decrease in tail flick latency in the oxaliplatin group compared to the vehicle group, the difference was not significant at weeks six and eight (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