Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction
- PMID: 16530964
- PMCID: PMC1805481
- DOI: 10.1016/j.pain.2006.01.037
Studies of peripheral sensory nerves in paclitaxel-induced painful peripheral neuropathy: evidence for mitochondrial dysfunction
Abstract
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.
Figures











Similar articles
-
Dynamic long-term microstructural and ultrastructural alterations in sensory nerves of rats of paclitaxel-induced neuropathic pain.Chin Med J (Engl). 2014;127(16):2945-52. Chin Med J (Engl). 2014. PMID: 25131233
-
Mitochondrial abnormality in sensory, but not motor, axons in paclitaxel-evoked painful peripheral neuropathy in the rat.Neuroscience. 2011 Dec 29;199:461-9. doi: 10.1016/j.neuroscience.2011.10.010. Epub 2011 Oct 19. Neuroscience. 2011. PMID: 22037390 Free PMC article.
-
Microtubule disorientation and axonal swelling in unmyelinated sensory axons during vincristine-induced painful neuropathy in rat.J Comp Neurol. 1998 Jun 15;395(4):481-92. J Comp Neurol. 1998. PMID: 9619501
-
Chemotherapy-induced peripheral neuropathy.Curr Neurol Neurosci Rep. 2008 Jan;8(1):56-65. doi: 10.1007/s11910-008-0010-5. Curr Neurol Neurosci Rep. 2008. PMID: 18367040 Review.
-
Pathogenesis of paclitaxel-induced peripheral neuropathy: A current review of in vitro and in vivo findings using rodent and human model systems.Exp Neurol. 2020 Feb;324:113121. doi: 10.1016/j.expneurol.2019.113121. Epub 2019 Nov 21. Exp Neurol. 2020. PMID: 31758983 Free PMC article. Review.
Cited by
-
Duloxetine hydrochloride loaded film forming dermal gel enriched with methylcobalamin and geranium oil attenuates paclitaxel-induced peripheral neuropathy in rats.IBRO Rep. 2020 Jul 15;9:85-95. doi: 10.1016/j.ibror.2020.07.006. eCollection 2020 Dec. IBRO Rep. 2020. PMID: 32760845 Free PMC article.
-
Neuropathy is not associated with clinical outcomes in patients receiving adjuvant taxane-containing therapy for operable breast cancer.J Clin Oncol. 2012 Sep 1;30(25):3051-7. doi: 10.1200/JCO.2011.39.8446. Epub 2012 Jul 30. J Clin Oncol. 2012. PMID: 22851566 Free PMC article. Clinical Trial.
-
Flavonoids Alleviate Peripheral Neuropathy Induced by Anticancer Drugs.Cancers (Basel). 2021 Mar 29;13(7):1576. doi: 10.3390/cancers13071576. Cancers (Basel). 2021. PMID: 33805565 Free PMC article. Review.
-
Expression of mitochondrial dysfunction-related genes and pathways in paclitaxel-induced peripheral neuropathy in breast cancer survivors.Mol Pain. 2018 Jan-Dec;14:1744806918816462. doi: 10.1177/1744806918816462. Epub 2018 Nov 14. Mol Pain. 2018. PMID: 30426838 Free PMC article.
-
Evodiamine ameliorates paclitaxel-induced neuropathic pain by inhibiting inflammation and maintaining mitochondrial anti-oxidant functions.Hum Cell. 2019 Jul;32(3):251-259. doi: 10.1007/s13577-019-00238-4. Epub 2019 Jan 30. Hum Cell. 2019. PMID: 30701373
References
-
- Andre N, Braguer D, Brasseur G, Goncalves A, Lemesle-Meunier D, Guise S, et al. Paclitaxel induces release of cytochrome c from mitochondria isolated from human neuroblastoma cells. Cancer Res. 2000;60:5349–53. - PubMed
-
- Authier N, Gillet JP, Fialip J, Eschalier A, Coudore F. Description of a short-term Taxol-induced nociceptive neuropathy in rats. Brain Res. 2000;887:239–49. - PubMed
-
- Brewer PA, Lynch K. Stimulation-associated changes in frog neuro-muscular junctions. A quantitative ultrastructural comparison of rapid-frozen, chemically fixed nerve terminals. Neuroscience. 1986;17:881–95. - PubMed
-
- Campana WM, Eskeland N, Calcutt NA, Misasi R, Myers RR, O’Brien JS. Prosaptide prevents paclitaxel neurotoxicity. Neurotoxicology. 1998;19:237–44. - PubMed
-
- Carre M, Andre N, Carles G, Borghi H, Brichese L, Briand C, et al. Tubulin is an inherent component of mitochondrial membranes that interacts with the voltage-dependent anion channel. J Biol Chem. 2002;277:33664–9. - PubMed
Publication types
MeSH terms
Substances
Grants and funding
LinkOut - more resources
Full Text Sources
Other Literature Sources
Medical
Miscellaneous