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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 induces nucleolar segregation and axonopathy. (a, b) Light microscopy revealed that DRG neurons from mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (b; n = 3) had segregated nucleoli (arrow heads) that were eccentric (black arrow) compared to DRGs from naïve mice (a; n = 3). (c, d) Electron microscopy also showed segregated nucleoli in DRG neurons from oxaliplatin-treated mice (d; n = 3) but not naïve mice (c; n = 3). Light microscope examination demonstrated that myelinated fibers in the sciatic nerve of mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (f; n = 3) had evidence of changes indicative of axonopathy (white arrows) that were not found in sciatic nerve from naïve mice (e; n = 3).
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Figure 4: Oxaliplatin induces nucleolar segregation and axonopathy. (a, b) Light microscopy revealed that DRG neurons from mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (b; n = 3) had segregated nucleoli (arrow heads) that were eccentric (black arrow) compared to DRGs from naïve mice (a; n = 3). (c, d) Electron microscopy also showed segregated nucleoli in DRG neurons from oxaliplatin-treated mice (d; n = 3) but not naïve mice (c; n = 3). Light microscope examination demonstrated that myelinated fibers in the sciatic nerve of mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (f; n = 3) had evidence of changes indicative of axonopathy (white arrows) that were not found in sciatic nerve from naïve mice (e; n = 3).

Mentions: Next, we wanted to determine whether the altered function of peripheral neurons after oxaliplatin was accompanied by structural changes in the DRG cell bodies and axons of the sciatic nerve. For this purpose, thin sections through the L4-L5 DRGs and sciatic nerve from naïve and oxaliplatin-treated mice were examined at the light and electron microscope levels two days after the final dose of drug in week four (Figure 4). Light microscopy revealed that DRG neurons from oxaliplatin-treated mice had a high incidence of multinucleolated cell bodies (Figure 4b arrowheads) with eccentric nucleoli (Figure 4b black arrow) compared to naïve DRG neurons (Figure 4a). In both experimental groups, the cytoplasm of neurons and satellite cells appears normal. The small circular structures with black borders that are evident between the cell bodies in Figure 4b are radicular fibers crossing the DRG. These findings were verified by electron microscopy, which showed nucleolar segregation in DRG neurons from oxaliplatin-treated (Figure 4d arrowheads) but not naïve mice (Figure 4c). Examination of sciatic nerves by light microscope showed that myelinated fibers in the sciatic nerve of oxaliplatin-treated mice (Figure 4f, white arrows) had mild changes indicative of axonopathy, which were not evident in sciatic nerve from naïve mice (Figure 4e). There were no changes evident in the unmyelinated fibers from either group.


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 induces nucleolar segregation and axonopathy. (a, b) Light microscopy revealed that DRG neurons from mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (b; n = 3) had segregated nucleoli (arrow heads) that were eccentric (black arrow) compared to DRGs from naïve mice (a; n = 3). (c, d) Electron microscopy also showed segregated nucleoli in DRG neurons from oxaliplatin-treated mice (d; n = 3) but not naïve mice (c; n = 3). Light microscope examination demonstrated that myelinated fibers in the sciatic nerve of mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (f; n = 3) had evidence of changes indicative of axonopathy (white arrows) that were not found in sciatic nerve from naïve mice (e; n = 3).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: Oxaliplatin induces nucleolar segregation and axonopathy. (a, b) Light microscopy revealed that DRG neurons from mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (b; n = 3) had segregated nucleoli (arrow heads) that were eccentric (black arrow) compared to DRGs from naïve mice (a; n = 3). (c, d) Electron microscopy also showed segregated nucleoli in DRG neurons from oxaliplatin-treated mice (d; n = 3) but not naïve mice (c; n = 3). Light microscope examination demonstrated that myelinated fibers in the sciatic nerve of mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (f; n = 3) had evidence of changes indicative of axonopathy (white arrows) that were not found in sciatic nerve from naïve mice (e; n = 3).
Mentions: Next, we wanted to determine whether the altered function of peripheral neurons after oxaliplatin was accompanied by structural changes in the DRG cell bodies and axons of the sciatic nerve. For this purpose, thin sections through the L4-L5 DRGs and sciatic nerve from naïve and oxaliplatin-treated mice were examined at the light and electron microscope levels two days after the final dose of drug in week four (Figure 4). Light microscopy revealed that DRG neurons from oxaliplatin-treated mice had a high incidence of multinucleolated cell bodies (Figure 4b arrowheads) with eccentric nucleoli (Figure 4b black arrow) compared to naïve DRG neurons (Figure 4a). In both experimental groups, the cytoplasm of neurons and satellite cells appears normal. The small circular structures with black borders that are evident between the cell bodies in Figure 4b are radicular fibers crossing the DRG. These findings were verified by electron microscopy, which showed nucleolar segregation in DRG neurons from oxaliplatin-treated (Figure 4d arrowheads) but not naïve mice (Figure 4c). Examination of sciatic nerves by light microscope showed that myelinated fibers in the sciatic nerve of oxaliplatin-treated mice (Figure 4f, white arrows) had mild changes indicative of axonopathy, which were not evident in sciatic nerve from naïve mice (Figure 4e). There were no changes evident in the unmyelinated fibers from either group.

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