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.
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.
aDepartment of Anesthesia, McGill University, Montréal, Québec, Canada
bThe Alan Edwards Centre for Research on Pain, McGill University, Montréal, Québec, Canada
cFaculty of Dentistry, McGill University, Montréal, Québec, Canada
*Corresponding author. Address: Anesthesia Research Unit, McGill University, McIntyre Bldg. Room 1202, 3655 Promenade Sir Wm. Osler, Montréal, Québec, Canada H3G 1Y6. Tel.: +1 514 398 3432.
Submitted September 6, 2011; revised November 16, 2011; accepted December 10, 2011.