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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) decreases NCV in caudal and digital nerves. (a) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (gray bars; n = 8) had a significant decrease in caudal NCV compared to naïve mice (black bars; n = 8). (b) The oxaliplatin-treated mice had a significant decrease in caudal nerve action potential amplitude compared to naïve mice. (c) The oxaliplatin-treated mice had a significant decrease in digital NCV compared to naïve mice. (d) The oxaliplatin-treated mice had no difference in the amplitude of the digital nerve action potential compared to naïve mice. **p < 0.0001 vs. naive, #p < 0.001 vs. naive, Student's T Test.
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Figure 3: Oxaliplatin (OHP) decreases NCV in caudal and digital nerves. (a) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (gray bars; n = 8) had a significant decrease in caudal NCV compared to naïve mice (black bars; n = 8). (b) The oxaliplatin-treated mice had a significant decrease in caudal nerve action potential amplitude compared to naïve mice. (c) The oxaliplatin-treated mice had a significant decrease in digital NCV compared to naïve mice. (d) The oxaliplatin-treated mice had no difference in the amplitude of the digital nerve action potential compared to naïve mice. **p < 0.0001 vs. naive, #p < 0.001 vs. naive, Student's T Test.

Mentions: After establishing that this mouse model exhibits a pain phenotype, we next wanted to determine whether alterations in peripheral nerve function could be contributing to the development of oxaliplatin-induced allodynia. To assess the functional status of peripheral neurons after chronic oxaliplatin treatment, the mice were randomly assigned to experimental groups. NCV and action potential amplitude were measured in the caudal and digital nerves 4 days after the final oxaliplatin dose in week four (Figure 3). Chronic oxaliplatin treatment induced a significant decrease in the caudal NCV (Figure 3a; p < 0.0001) with a concomitant significant decrease in action potential amplitude (Figure 3b; p < 0.01) compared to the naïve group. After oxaliplatin, the digital NCV also significantly decreased (Figure 3c; p < 0.001), though the action potential amplitude was not different (Figure 3d), compared to the naïve 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 (OHP) decreases NCV in caudal and digital nerves. (a) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (gray bars; n = 8) had a significant decrease in caudal NCV compared to naïve mice (black bars; n = 8). (b) The oxaliplatin-treated mice had a significant decrease in caudal nerve action potential amplitude compared to naïve mice. (c) The oxaliplatin-treated mice had a significant decrease in digital NCV compared to naïve mice. (d) The oxaliplatin-treated mice had no difference in the amplitude of the digital nerve action potential compared to naïve mice. **p < 0.0001 vs. naive, #p < 0.001 vs. naive, Student's T Test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: Oxaliplatin (OHP) decreases NCV in caudal and digital nerves. (a) Mice treated with oxaliplatin 3.5 mg/kg/iv twice weekly for four weeks (gray bars; n = 8) had a significant decrease in caudal NCV compared to naïve mice (black bars; n = 8). (b) The oxaliplatin-treated mice had a significant decrease in caudal nerve action potential amplitude compared to naïve mice. (c) The oxaliplatin-treated mice had a significant decrease in digital NCV compared to naïve mice. (d) The oxaliplatin-treated mice had no difference in the amplitude of the digital nerve action potential compared to naïve mice. **p < 0.0001 vs. naive, #p < 0.001 vs. naive, Student's T Test.
Mentions: After establishing that this mouse model exhibits a pain phenotype, we next wanted to determine whether alterations in peripheral nerve function could be contributing to the development of oxaliplatin-induced allodynia. To assess the functional status of peripheral neurons after chronic oxaliplatin treatment, the mice were randomly assigned to experimental groups. NCV and action potential amplitude were measured in the caudal and digital nerves 4 days after the final oxaliplatin dose in week four (Figure 3). Chronic oxaliplatin treatment induced a significant decrease in the caudal NCV (Figure 3a; p < 0.0001) with a concomitant significant decrease in action potential amplitude (Figure 3b; p < 0.01) compared to the naïve group. After oxaliplatin, the digital NCV also significantly decreased (Figure 3c; p < 0.001), though the action potential amplitude was not different (Figure 3d), compared to the naïve 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