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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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Related in: MedlinePlus

Body weight decreases after oxaliplatin (OHP) treatment. Mice treated with oxaliplatin3.5 mg/kg/iv twice weekly (n = 8) lost a significant amount of body weight compared to naïve mice (n = 8) °p < 0.05, * p < 0.01, ** p < 0.0001 vs. naïve, ANOVA with repeated measures.
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Figure 1: Body weight decreases after oxaliplatin (OHP) treatment. Mice treated with oxaliplatin3.5 mg/kg/iv twice weekly (n = 8) lost a significant amount of body weight compared to naïve mice (n = 8) °p < 0.05, * p < 0.01, ** p < 0.0001 vs. naïve, ANOVA with repeated measures.

Mentions: To generate the model of oxaliplatin-induced painful peripheral neuropathy used in this study, the mice were given tail vein injections of oxaliplatin (3.5 mg/kg) twice weekly (separated by either 3 or 4 days) for four weeks. The control group was naïve mice that did not receive drug or vehicle injections. The duration of this study was 30 days, during which the mice were continuously allodynic after receiving oxaliplatin. The oxaliplatin was generally well-tolerated by the mice. They continued to groom, make nests, explore their surroundings and climb on their wire cage tops during the course of drug treatment, though approximately 20% showed signs of mild kyphosis and piloerection. The mice were weighed on drug administration days and, over the course of the study, the oxaliplatin-treated mice had a significant decrease in body weight compared to the naïve mice (Figure 1; day 4, p < 0.05; days 12 and 17, p < 0.01; days 20, 23, 27, p < 0.0001), reaching 15% by the completion of the study. No mice were euthanized prematurely during the course of the study.


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)

Body weight decreases after oxaliplatin (OHP) treatment. Mice treated with oxaliplatin3.5 mg/kg/iv twice weekly (n = 8) lost a significant amount of body weight compared to naïve mice (n = 8) °p < 0.05, * p < 0.01, ** p < 0.0001 vs. naïve, ANOVA with repeated measures.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Body weight decreases after oxaliplatin (OHP) treatment. Mice treated with oxaliplatin3.5 mg/kg/iv twice weekly (n = 8) lost a significant amount of body weight compared to naïve mice (n = 8) °p < 0.05, * p < 0.01, ** p < 0.0001 vs. naïve, ANOVA with repeated measures.
Mentions: To generate the model of oxaliplatin-induced painful peripheral neuropathy used in this study, the mice were given tail vein injections of oxaliplatin (3.5 mg/kg) twice weekly (separated by either 3 or 4 days) for four weeks. The control group was naïve mice that did not receive drug or vehicle injections. The duration of this study was 30 days, during which the mice were continuously allodynic after receiving oxaliplatin. The oxaliplatin was generally well-tolerated by the mice. They continued to groom, make nests, explore their surroundings and climb on their wire cage tops during the course of drug treatment, though approximately 20% showed signs of mild kyphosis and piloerection. The mice were weighed on drug administration days and, over the course of the study, the oxaliplatin-treated mice had a significant decrease in body weight compared to the naïve mice (Figure 1; day 4, p < 0.05; days 12 and 17, p < 0.01; days 20, 23, 27, p < 0.0001), reaching 15% by the completion of the study. No mice were euthanized prematurely during the course of the study.

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