Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction

Pain. 2006 Jun;122(3):245-257. doi: 10.1016/j.pain.2006.01.037. Epub 2006 Mar 13.


Paclitaxel chemotherapy frequently induces neuropathic pain during and often persisting after therapy. The mechanisms responsible for this pain are unknown. Using a rat model of paclitaxel-induced painful peripheral neuropathy, we have performed studies to search for peripheral nerve pathology. Paclitaxel-induced mechano-allodynia and mechano-hyperalgesia were evident after a short delay, peaked at day 27 and finally resolved on day 155. Paclitaxel- and vehicle-treated rats were perfused on days 7, 27 and 160. Portions of saphenous nerves were processed for electron microscopy. There was no evidence of paclitaxel-induced degeneration or regeneration as myelin structure was normal and the number/density of myelinated axons and C-fibres was unaltered by paclitaxel treatment at any time point. In addition, the prevalence of ATF3-positive dorsal root ganglia cells was normal in paclitaxel-treated animals. With one exception, at day 160 in myelinated axons, total microtubule densities were also unaffected by paclitaxel both in C-fibres and myelinated axons. C-fibres were significantly swollen following paclitaxel at days 7 and 27 compared to vehicle. The most striking finding was significant increases in the prevalence of atypical (swollen and vacuolated) mitochondria in both C-fibres (1.6- to 2.3-fold) and myelinated axons (2.4- to 2.6-fold) of paclitaxel-treated nerves at days 7 and 27. Comparable to the pain behaviour, these mitochondrial changes had resolved by day 160. Our data do not support a causal role for axonal degeneration or dysfunction of axonal microtubules in paclitaxel-induced pain. Instead, our data suggest that a paclitaxel-induced abnormality in axonal mitochondria of sensory nerves contributes to paclitaxel-induced pain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic* / pharmacology
  • Axons / ultrastructure
  • Behavior, Animal
  • Male
  • Microscopy, Electron
  • Microtubules / drug effects
  • Microtubules / ultrastructure
  • Mitochondria* / drug effects
  • Mitochondria* / ultrastructure
  • Nerve Fibers, Unmyelinated / drug effects
  • Nerve Fibers, Unmyelinated / ultrastructure
  • Neurons, Afferent* / drug effects
  • Neurons, Afferent* / ultrastructure
  • Paclitaxel* / pharmacology
  • Pain / physiopathology
  • Pain / psychology
  • Peripheral Nerves / pathology
  • Peripheral Nerves / physiopathology*
  • Peripheral Nervous System Diseases / chemically induced*
  • Peripheral Nervous System Diseases / pathology
  • Peripheral Nervous System Diseases / physiopathology*
  • Peripheral Nervous System Diseases / psychology
  • Rats
  • Rats, Sprague-Dawley


  • Antineoplastic Agents, Phytogenic
  • Paclitaxel