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

Natalie A Duggett,Sarah J.L Flatters,Lisa A Griffiths

doi:10.1097/j.pain.0000000000000939

Natalie A Duggett, Sarah J.L Flatters + Show 1 more

Open Access

https://doi.org/10.1097/j.pain.0000000000000939

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Journal: Pain	Publication Date: May 2, 2017
Citations: 83	License type: CC BY 4.0

Affiliation: King's College London, Creative Commons

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.

Highlights

Paclitaxel is a first-line taxane-derived chemotherapeutic agent commonly used in the treatment of breast and ovarian cancers
We have examined oxidative phosphorylation, glycolysis, and Adenosine diphosphate (ADP)/ adenosine triphosphate (ATP) levels to understand how the main energy producing pathways alter prior to, during, and at the resolution of paclitaxel-induced pain in dorsal root ganglion (DRG) neurons
At day 7, 24 hours after the last paclitaxel administration and prior to marked pain behaviour, both maximal respiration and spare reserve capacity were significantly impaired in DRG neurons isolated from paclitaxel-treated rats

Summary

Introduction

Paclitaxel is a first-line taxane-derived chemotherapeutic agent commonly used in the treatment of breast and ovarian cancers. The clinical use of paclitaxel is impeded by peripheral neuropathy, which remains the main dose-limiting side effect because of the current lack of preventative or treatment approaches (reviewed in Ref. 16). Patients typically report numbness, tingling, spontaneous pain, and evoked pain to mechanical and cold stimuli in their hands and feet.[3,5,23] Recent meta-analysis showed that. · · August 2017 Volume 158 Number 8 paclitaxel-induced peripheral neuropathy affected 44% to 98% of patients.[25] neuropathy can persist for months or years after the paclitaxel treatment ends.[5,25,28] paclitaxel treatment is a significant cause of sensory abnormalities and chronic pain substantially affecting quality of life.[27]

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