Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction.
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.
Flatters
Sarah J L
SJL
Anaesthesia Research Unit, McGill University, Montreal, Que., Canada Faculty of Dentistry, McGill University, Montreal, Que., Canada Centre for Research on Pain, McGill University, Montreal, Que., Canada.
Bennett
Gary J
GJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D001369:Axons / Q000648:ultrastructure; D001522:Behavior, Animal; D008297:Male; D008854:Microscopy, Electron; D008870:Microtubules / Q000187:drug effects / Q000648:ultrastructure; D008928:Mitochondria / Q000187:drug effects / Q000648:ultrastructure; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000648:ultrastructure; D009475:Neurons, Afferent / Q000187:drug effects / Q000648:ultrastructure; D017239:Paclitaxel / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000523:psychology; D010525:Peripheral Nerves / Q000473:pathology / Q000503:physiopathology*; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology* / Q000523:psychology; D051381:Rats; D017207:Rats, Sprague-Dawley
D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel