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Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice.

Renn CL, Carozzi VA, Rhee P, Gallop D, Dorsey SG, Cavaletti G - Mol Pain (2011)

Bottom Line: To further characterize the model, we examined nocifensive behavior and central nervous system excitability by in vivo electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli.Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH.Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Nursing, Center for Pain Studies, University of Maryland, Baltimore, MD, USA. renn@son.umaryland.edu

ABSTRACT

Background: A major clinical issue affecting 10-40% of cancer patients treated with oxaliplatin is severe peripheral neuropathy with symptoms including cold sensitivity and neuropathic pain. Rat models have been used to describe the pathological features of oxaliplatin-induced peripheral neuropathy; however, they are inadequate for parallel studies of oxaliplatin's antineoplastic activity and neurotoxicity because most cancer models are developed in mice. Thus, we characterized the effects of chronic, bi-weekly administration of oxaliplatin in BALB/c mice. We first studied oxaliplatin's effects on the peripheral nervous system by measuring caudal and digital nerve conduction velocities (NCV) followed by ultrastructural and morphometric analyses of dorsal root ganglia (DRG) and sciatic nerves. To further characterize the model, we examined nocifensive behavior and central nervous system excitability by in vivo electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice

Results: We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli. Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH.

Conclusions: Our findings demonstrate that chronic treatment with oxaliplatin produces neurotoxic changes in BALB/c mice, confirming that this model is a suitable tool to conduct further mechanistic studies of oxaliplatin-related antineoplastic activity, peripheral neurotoxicity and pain. Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.

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Oxaliplatin (OHP) induces mechanical and cold allodynia but not heat hyperalgesia. (a) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had a significant decrease in mechanical threshold from baseline and compared to naïve mice (n = 8) that started after the first week of treatment and persisted for at least four weeks. **p < 0.001 vs. baseline, Friedman Test; #p < 0.001 vs. naïve, Mann Whitney U Test. (b) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had a significant increase in cold threshold from baseline and compared to naïve mice (n = 8) that started after the first week of treatment and persisted for at least four weeks. *p < 0.01 vs. baseline, ANOVA with Repeated Measures; #p < 0.05 vs. naïve, Student's T Test. (c) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had no change heat threshold from baseline and were not different from naïve mice throughout the duration of the experiment. P > 0.05 vs. baseline, ANOVA with Repeated Measures; p > 0.05 vs. naïve, Student's T Test.
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Figure 2: Oxaliplatin (OHP) induces mechanical and cold allodynia but not heat hyperalgesia. (a) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had a significant decrease in mechanical threshold from baseline and compared to naïve mice (n = 8) that started after the first week of treatment and persisted for at least four weeks. **p < 0.001 vs. baseline, Friedman Test; #p < 0.001 vs. naïve, Mann Whitney U Test. (b) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had a significant increase in cold threshold from baseline and compared to naïve mice (n = 8) that started after the first week of treatment and persisted for at least four weeks. *p < 0.01 vs. baseline, ANOVA with Repeated Measures; #p < 0.05 vs. naïve, Student's T Test. (c) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had no change heat threshold from baseline and were not different from naïve mice throughout the duration of the experiment. P > 0.05 vs. baseline, ANOVA with Repeated Measures; p > 0.05 vs. naïve, Student's T Test.

Mentions: Mechanical allodynia was defined as a decrease in paw withdrawal threshold (g) from baseline. The oxaliplatin-treated mice had a significant decrease in mechanical threshold after the first week of oxaliplatin treatment compared to baseline that persisted for at least four weeks (Figure 2a; Chi Sq. 17.36, df 4, p < 0.001), while the naïve mice did not (Chi Sq. 0.49, df 4, p > 0.05). Further, the oxaliplatin-treated mice had a significantly lower mechanical threshold than the naïve mice after the first week of oxaliplatin treatment that persisted for at least four weeks (p < 0.001).


Multimodal assessment of painful peripheral neuropathy induced by chronic oxaliplatin-based chemotherapy in mice.

Renn CL, Carozzi VA, Rhee P, Gallop D, Dorsey SG, Cavaletti G - Mol Pain (2011)

Oxaliplatin (OHP) induces mechanical and cold allodynia but not heat hyperalgesia. (a) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had a significant decrease in mechanical threshold from baseline and compared to naïve mice (n = 8) that started after the first week of treatment and persisted for at least four weeks. **p < 0.001 vs. baseline, Friedman Test; #p < 0.001 vs. naïve, Mann Whitney U Test. (b) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had a significant increase in cold threshold from baseline and compared to naïve mice (n = 8) that started after the first week of treatment and persisted for at least four weeks. *p < 0.01 vs. baseline, ANOVA with Repeated Measures; #p < 0.05 vs. naïve, Student's T Test. (c) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had no change heat threshold from baseline and were not different from naïve mice throughout the duration of the experiment. P > 0.05 vs. baseline, ANOVA with Repeated Measures; p > 0.05 vs. naïve, Student's T Test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3105941&req=5

Figure 2: Oxaliplatin (OHP) induces mechanical and cold allodynia but not heat hyperalgesia. (a) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had a significant decrease in mechanical threshold from baseline and compared to naïve mice (n = 8) that started after the first week of treatment and persisted for at least four weeks. **p < 0.001 vs. baseline, Friedman Test; #p < 0.001 vs. naïve, Mann Whitney U Test. (b) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had a significant increase in cold threshold from baseline and compared to naïve mice (n = 8) that started after the first week of treatment and persisted for at least four weeks. *p < 0.01 vs. baseline, ANOVA with Repeated Measures; #p < 0.05 vs. naïve, Student's T Test. (c) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly (n = 8) had no change heat threshold from baseline and were not different from naïve mice throughout the duration of the experiment. P > 0.05 vs. baseline, ANOVA with Repeated Measures; p > 0.05 vs. naïve, Student's T Test.
Mentions: Mechanical allodynia was defined as a decrease in paw withdrawal threshold (g) from baseline. The oxaliplatin-treated mice had a significant decrease in mechanical threshold after the first week of oxaliplatin treatment compared to baseline that persisted for at least four weeks (Figure 2a; Chi Sq. 17.36, df 4, p < 0.001), while the naïve mice did not (Chi Sq. 0.49, df 4, p > 0.05). Further, the oxaliplatin-treated mice had a significantly lower mechanical threshold than the naïve mice after the first week of oxaliplatin treatment that persisted for at least four weeks (p < 0.001).

Bottom Line: To further characterize the model, we examined nocifensive behavior and central nervous system excitability by in vivo electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli.Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH.Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Nursing, Center for Pain Studies, University of Maryland, Baltimore, MD, USA. renn@son.umaryland.edu

ABSTRACT

Background: A major clinical issue affecting 10-40% of cancer patients treated with oxaliplatin is severe peripheral neuropathy with symptoms including cold sensitivity and neuropathic pain. Rat models have been used to describe the pathological features of oxaliplatin-induced peripheral neuropathy; however, they are inadequate for parallel studies of oxaliplatin's antineoplastic activity and neurotoxicity because most cancer models are developed in mice. Thus, we characterized the effects of chronic, bi-weekly administration of oxaliplatin in BALB/c mice. We first studied oxaliplatin's effects on the peripheral nervous system by measuring caudal and digital nerve conduction velocities (NCV) followed by ultrastructural and morphometric analyses of dorsal root ganglia (DRG) and sciatic nerves. To further characterize the model, we examined nocifensive behavior and central nervous system excitability by in vivo electrophysiological recording of spinal dorsal horn (SDH) wide dynamic range neurons in oxaliplatin-treated mice

Results: We found significantly decreased NCV and action potential amplitude after oxaliplatin treatment along with neuronal atrophy and multinucleolated DRG neurons that have eccentric nucleoli. Oxaliplatin also induced significant mechanical allodynia and cold hyperalgesia, starting from the first week of treatment, and a significant increase in the activity of wide dynamic range neurons in the SDH.

Conclusions: Our findings demonstrate that chronic treatment with oxaliplatin produces neurotoxic changes in BALB/c mice, confirming that this model is a suitable tool to conduct further mechanistic studies of oxaliplatin-related antineoplastic activity, peripheral neurotoxicity and pain. Further, this model can be used for the preclinical discovery of new neuroprotective and analgesic compounds.

Show MeSH
Related in: MedlinePlus