Paclitaxel-induced painful neuropathy is associated with changes in mitochondrial bioenergetics, glycolysis, and an energy deficit in dorsal root ganglia neurons

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Abstract

Painful neuropathy is the major dose-limiting side effect of paclitaxel chemotherapy. Mitochondrial dysfunction and adenosine
triphosphate (ATP) deficit have previously been shown in peripheral nerves of paclitaxel-treated rats, but the effects of paclitaxel in
the dorsal root ganglia (DRGs) have not been explored. The aim of this study was to determine the bioenergetic status of DRG
neurons following paclitaxel exposure in vitro and in vivo. Utilising isolated DRG neurons, we measured respiratory function under
basal conditions and at maximal capacity, glycolytic function, and Adenosine diphosphate (ADP)/ATP levels at 3 key behavioural
timepoints; prior to pain onset (day 7), peak pain severity and pain resolution. At day 7, maximal respiration and spare reserve
capacity were significantly decreased in DRG neurons from paclitaxel-treated rats. This was accompanied by decreased basal ATP
levels and unaltered ADP levels. At peak pain severity, respiratory function was unaltered, yet glycolytic function was significantly
increased. Reduced ATP and unaltered ADP levels were also observed at the peak pain timepoint. All these effects in DRG neurons
had dissipated by the pain resolution timepoint. None of these paclitaxel-evoked changes could be replicated from in vitro paclitaxel
exposure to naive DRG neurons, demonstrating the impact of in vivo exposure and the importance of in vivo models. These data
demonstrate the nature of mitochondrial dysfunction evoked by in vivo paclitaxel in the DRG for the first time. Furthermore, we have
identified paclitaxel-evoked changes in the bioenergetics of DRG neurons, which result in a persistent energy deficit that is causal to
the development and maintenance of paclitaxel-induced pain.
Original languageEnglish
Pages (from-to)1499-1508
JournalPain
Volume158
Issue number8
Early online date28 Apr 2017
DOIs
Publication statusPublished - Aug 2017

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