Abstract
The major dose-limiting effect of paclitaxel anticancer treatment is a persistent peripheral sensory neuropathy. Patients typically report numbness, tingling, and ongoing and evoked pain in a stocking-and-glove distribution. Paclitaxel-induced painful peripheral neuropathy (PIPPN) can be induced in adult male Sprague-Dawley rats by intraperitoneal administration of 2mg/kg paclitaxel on days 0, 2, 4 and 6. Using this model, we have demonstrated thatpaclitaxel-treated rats develop robust and long-lasting mechanical and cold hypersensitivities, decreased burrowing activity indicative of ongoing pain, in the absence of heat sensitivity, motor incoordination, and signs of ill health. This clinically relevant rat model of PIPPN was further validated by demonstrating that ethosuximide reversed paclitaxel-induced mechanical hypersensitivity, as has been shown previously by others.
Previous work revealed atypical mitochondria in saphenous nerves of paclitaxel-treated rats. Given that mitochondria are a major source of reactive oxygen species (ROS), the major aim of this PhD was to investigate paclitaxel’s effect on mitochondrial ROS production, and to show a temporal and tissue-specific link between increased ROS production and paclitaxelinduced pain. Studies focused on three key time points: day 7, after paclitaxel administration but prior to pain onset; peak pain; and pain resolution, and effects of paclitaxel were
compared to a concurrent vehicle-treated control group. The major findings are as follows. Development of paclitaxel-induced mechanical hypersensitivity is attenuated by mitochondrial complex III inhibition with antimycin A, and established mechanical hypersensitivity is inhibited by PBN, a ROS scavenger, and rotenone or antimycin A to inhibit mitochondrial complex I or
III, respectively. At day 7, ROS production is increased in dorsal horn neurons and 4- hydroxynonenal, a marker of oxidative stress, is decreased in saphenous nerve. At day 7 in DRG neurons, there is a reduction in spare reserve capacity and maximal respiration. Increased citrate synthase levels and ROS production in non-peptidergic neurons is seen at day 7 and peak pain. Increases in mitochondrial complex IV activity, as well as an apparent increase in glycolysis, are seen at peak pain. Mitochondrial membrane potential, and levels of
voltage-dependent anion channel (VDAC), complex I and complex IV are unchanged over the time course. Therefore, these studies provide further evidence for a causal role of mitochondrial ROS and mitochondrial dysfunction in paclitaxel-induced pain in the rat.
| Date of Award | 2014 |
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| Original language | English |
| Awarding Institution |
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| Supervisor | Sarah Flatters (Supervisor) & Stuart Bevan (Supervisor) |