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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) treatment causes decreased the area of DRG cell body and nucleolus. Morphometric analysis revealed that DRG neurons from mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (n = 3) had a significant decrease in the area (mm2) of the cell bodies (a) and nucleoli (c) compared to DRG neurons from naïve mice (n = 3). (b) There was no difference in the areas of the nuclei from oxaliplatin-treated and naïve mice. °p < 0.05 vs naïve, #p < 0.001 vs naïve, Student's T Test.
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Figure 5: Oxaliplatin (OHP) treatment causes decreased the area of DRG cell body and nucleolus. Morphometric analysis revealed that DRG neurons from mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (n = 3) had a significant decrease in the area (mm2) of the cell bodies (a) and nucleoli (c) compared to DRG neurons from naïve mice (n = 3). (b) There was no difference in the areas of the nuclei from oxaliplatin-treated and naïve mice. °p < 0.05 vs naïve, #p < 0.001 vs naïve, Student's T Test.

Mentions: Our previous work in rat models demonstrated that platinum-derived compounds induce DRG neuron cell body shrinkage [7,16,17]. Since finding that oxaliplatin induced changes to the nucleoli of DRG neurons in our mouse model, we performed a morphometric analysis to examine the cell bodies of DRG neurons from oxaliplatin-treated (3.5 mg/kg/iv twice weekly for four weeks) and naïve control mice for evidence of cell body shrinkage similar to that seen in rats. The morphometric analysis revealed that DRG neurons from oxaliplatin-treated mice (gray bars) had a significant decrease in the area (mm2) of their cell bodies (Figure 5a; p < 0.05) and nucleoli (Figure 5c; p < 0.001), but not nuclei, compared to DRG neurons from naïve mice (black bars).


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) treatment causes decreased the area of DRG cell body and nucleolus. Morphometric analysis revealed that DRG neurons from mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (n = 3) had a significant decrease in the area (mm2) of the cell bodies (a) and nucleoli (c) compared to DRG neurons from naïve mice (n = 3). (b) There was no difference in the areas of the nuclei from oxaliplatin-treated and naïve mice. °p < 0.05 vs naïve, #p < 0.001 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 5: Oxaliplatin (OHP) treatment causes decreased the area of DRG cell body and nucleolus. Morphometric analysis revealed that DRG neurons from mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (n = 3) had a significant decrease in the area (mm2) of the cell bodies (a) and nucleoli (c) compared to DRG neurons from naïve mice (n = 3). (b) There was no difference in the areas of the nuclei from oxaliplatin-treated and naïve mice. °p < 0.05 vs naïve, #p < 0.001 vs naïve, Student's T Test.
Mentions: Our previous work in rat models demonstrated that platinum-derived compounds induce DRG neuron cell body shrinkage [7,16,17]. Since finding that oxaliplatin induced changes to the nucleoli of DRG neurons in our mouse model, we performed a morphometric analysis to examine the cell bodies of DRG neurons from oxaliplatin-treated (3.5 mg/kg/iv twice weekly for four weeks) and naïve control mice for evidence of cell body shrinkage similar to that seen in rats. The morphometric analysis revealed that DRG neurons from oxaliplatin-treated mice (gray bars) had a significant decrease in the area (mm2) of their cell bodies (Figure 5a; p < 0.05) and nucleoli (Figure 5c; p < 0.001), but not nuclei, compared to DRG neurons from naïve mice (black bars).

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