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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) increases activity of wide dynamic range neurons in the spinal dorsal horn. Two days after the final injection of oxaliplatin 3.5 mg/kg/iv, the peak number of spikes per second were higher in the oxaliplatin-injected (gray bars) mice compared with naïve mice (black bars). **p < 0.001 and #p < 0.01 vs. naive, Student's T Test.
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Figure 7: Oxaliplatin (OHP) increases activity of wide dynamic range neurons in the spinal dorsal horn. Two days after the final injection of oxaliplatin 3.5 mg/kg/iv, the peak number of spikes per second were higher in the oxaliplatin-injected (gray bars) mice compared with naïve mice (black bars). **p < 0.001 and #p < 0.01 vs. naive, Student's T Test.

Mentions: After determining that chronic oxaliplatin treatment resulted in altered nocifensive behavior, peripheral nerve function and structural changes in DRG neuron cell bodies and sciatic nerve, our next question was to determine if there was a concomitant change in the activity of wide dynamic range neurons in the spinal dorsal horn. Two days after the mice received their final dose of oxaliplatin (3.5 mg/kg/iv twice weekly) in the fourth week, the activity of 43 deep dorsal horn neurons (20 neurons from 6 naive and 23 neurons from 6 oxaliplatin-treated mice; Table 1) was recorded and analyzed. Neurons were classified as wide dynamic range based on their response to innocuous and noxious mechanical stimuli applied to the plantar surface of the hind paw ipsilateral to the recording site (Figure 6). During stimulation, the number of spikes per second (Figure 7; Table 1) was significantly higher in the oxaliplatin-treated mice during the innocuous brush (64.93 ± 6.27 spikes/s), moderate pressure (70.59 ± 11.17 spikes/s), noxious pinch (123.38 ± 14.77 spikes/s) and acetone (43.09 ± 9.16 spikes/s) stimuli compared to the naive mice (24.47 ± 4.62, 25.78 ± 5.92, 46.56 ± 9.97, 13.92 ± 3.01 spikes/s respectively; p < 0.001 for brush, press, pinch; p < 0.01 for acetone).


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) increases activity of wide dynamic range neurons in the spinal dorsal horn. Two days after the final injection of oxaliplatin 3.5 mg/kg/iv, the peak number of spikes per second were higher in the oxaliplatin-injected (gray bars) mice compared with naïve mice (black bars). **p < 0.001 and #p < 0.01 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 7: Oxaliplatin (OHP) increases activity of wide dynamic range neurons in the spinal dorsal horn. Two days after the final injection of oxaliplatin 3.5 mg/kg/iv, the peak number of spikes per second were higher in the oxaliplatin-injected (gray bars) mice compared with naïve mice (black bars). **p < 0.001 and #p < 0.01 vs. naive, Student's T Test.
Mentions: After determining that chronic oxaliplatin treatment resulted in altered nocifensive behavior, peripheral nerve function and structural changes in DRG neuron cell bodies and sciatic nerve, our next question was to determine if there was a concomitant change in the activity of wide dynamic range neurons in the spinal dorsal horn. Two days after the mice received their final dose of oxaliplatin (3.5 mg/kg/iv twice weekly) in the fourth week, the activity of 43 deep dorsal horn neurons (20 neurons from 6 naive and 23 neurons from 6 oxaliplatin-treated mice; Table 1) was recorded and analyzed. Neurons were classified as wide dynamic range based on their response to innocuous and noxious mechanical stimuli applied to the plantar surface of the hind paw ipsilateral to the recording site (Figure 6). During stimulation, the number of spikes per second (Figure 7; Table 1) was significantly higher in the oxaliplatin-treated mice during the innocuous brush (64.93 ± 6.27 spikes/s), moderate pressure (70.59 ± 11.17 spikes/s), noxious pinch (123.38 ± 14.77 spikes/s) and acetone (43.09 ± 9.16 spikes/s) stimuli compared to the naive mice (24.47 ± 4.62, 25.78 ± 5.92, 46.56 ± 9.97, 13.92 ± 3.01 spikes/s respectively; p < 0.001 for brush, press, pinch; p < 0.01 for acetone).

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