Effects of mitochondrial poisons on the neuropathic pain produced by the chemotherapeutic agents, paclitaxel and oxaliplatin

Wen Hua Xiao, Gary J Bennett, Wen Hua Xiao, Gary J Bennett

Abstract

The dose-limiting side effect of taxane, platinum-complex, and other kinds of anticancer drugs is a chronic, distal, bilaterally symmetrical, sensory peripheral neuropathy that is often accompanied by neuropathic pain. Work with animal models of these conditions suggests that the neuropathy is a consequence of toxic effects on mitochondria in primary afferent sensory neurons. If this is true, then additional mitochondrial insult ought to make the neuropathic pain worse. This prediction was tested in rats with painful peripheral neuropathy due to the taxane agent, paclitaxel, and the platinum-complex agent, oxaliplatin. Rats with established neuropathy were given 1 of 3 mitochondrial poisons: rotenone (an inhibitor of respiratory Complex I), oligomycin (an inhibitor of adenosine triphosphate synthase), and auranofin (an inhibitor of the thioredoxin-thioredoxin reductase mitochondrial antioxidant defense system). All 3 toxins significantly increased the severity of paclitaxel-evoked and oxaliplatin-evoked mechano-allodynia and mechano-hyperalgesia while having no effect on the mechano-sensitivity of chemotherapy-naïve rats. Chemotherapy-evoked painful peripheral neuropathy is associated with an abnormal spontaneous discharge in primary afferent A fibers and C fibers. Oligomycin, at the same dose that exacerbated allodynia and hyperalgesia, significantly increased the discharge frequency of spontaneously discharging A fibers and C fibers in both paclitaxel-treated and oxaliplatin-treated rats, but did not evoke any discharge in naïve control rats. These results implicate mitochondrial dysfunction in the production of chemotherapy-evoked neuropathic pain and suggest that drugs that have positive effects on mitochondrial function may be of use in its treatment and prevention.

Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Effects of (A) rotenone, (B) oligomycin and (C) auranofin in paclitaxel-treated rats and naïve (no chemotherapy) controls. First column: mechano-allodynia (mean ± SEM response frequency to 4 g von Frey hair); second column: mechano-hyperalgesia (15 g von Frey hair). Pre/Post: before and after injection of mitotoxin or vehicle. ns: statistically non-significant; ** p < 0.01 compared to vehicle-injected group (Bonferroni-corrected t-tests).
Fig. 2
Fig. 2
Effects of (A) rotenone, (B) oligomycin and (C) auranofin in oxaliplatin-treated rats and naïve (no chemotherapy) controls. First column: mechano-allodynia (mean ± SEM response frequency to 4 g von Frey hair); second column: mechano-hyperalgesia (15 g von Frey hair). Pre/Post: before and after injection of mitotoxin or vehicle. ns: statistically non-significant; ** p < 0.01 compared to vehicle-injected group (Bonferroni-corrected t-tests).
Fig. 3
Fig. 3
Effects of oligomycin on chemotherapy-evoked abnormal spontaneous discharge in primary afferent axons in paclitaxel-treated and oxaliplatin-treated rats. Baseline discharge frequency (dashed line) was computed from the discharge rate seen in a 5 min epoch prior to injection and is set at 100%. (A) Effects on A-fibers after injection of oligomycin (paclitaxel-treated and oxaliplatin-treated rats, 10 fibers each) or vehicle (10 fibers; 5 each from paclitaxel-treated and oxaliplatin-treated rats) at time zero. (B) Effects on C-fibers after injection of oligomycin (paclitaxel-treated and oxaliplatin-treated rats, 7 fibers each) or vehicle injection (10 fibers; 5 each from paclitaxel-treated and oxaliplatin-treated rats). The oligomycin-evoked changes are statistically significant (p < 0.05) for both the paclitaxel-treated and oxaliplatin-treated A-fibers and C-fibers (ANOVA on the area-under-the-curve values followed by Dunnett’s t-test). The mitochondrial poisons, rotenone, oligomycin, and auranofin, significantly increase chemotherapy-evoked neuropathic pain at doses that have no effect on the responses of normal rats.

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