Paclitaxel potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through the combination of paclitaxel-induced increase in mitochondrial reactive oxygen species and diabetes-related overexpression of TRPA1.
Diabetes comorbidities include disabling peripheral neuropathy (DPN) and an increased risk of developing cancer. Antimitotic drugs, such as paclitaxel, are well known to facilitate the occurrence of peripheral neuropathy. Practitioners frequently observe the development or co-occurrence of enhanced DPN, especially cold sensitivity, in diabetic patients during chemotherapy. Preclinical studies showed that reactive oxygen species (ROS) and cold activate transient receptor potential ankyrin-1 (TRPA1) cation channels, which are involved in cold-evoked pain transduction signaling in DPN. Additionally, paclitaxel treatment has been associated with an accumulation of atypical mitochondria in the sensory nerves of rats. We hypothesized that paclitaxel might potentiate cold hyperalgesia by increasing mitochondrial injuries and TRPA1 activation. Thus, the kinetics of paclitaxel-induced cold hyperalgesia, mitochondrial ROS production, and TRPA1 expression were evaluated in dorsal root ganglia of normoglycemic and streptozotocin-induced diabetic rats. In diabetic rats, paclitaxel significantly enhanced cold hyperalgesia in comparison to normoglycemic paclitaxel-treated control rats. These effects were prevented by N-acetyl-cysteine, a reducing agent, and by HC030031, an antagonist of TRPA1. In diabetic and control rats, paclitaxel treatment was associated with an accumulation of atypical mitochondria and a 2-fold increase in mitochondrial ROS production. Moreover, mRNA levels of glutathione peroxidase 4 and glutathione-S-reductase were significantly lower in diabetic groups treated with paclitaxel. Finally, TRPA1 gene expression was enhanced by 45% in diabetic rats. Paclitaxel potentiation of cold hyperalgesia in diabetes may result from the combination of increased mitochondrial ROS production and poor radical detoxification induced by paclitaxel treatment and diabetes-related overexpression of TRPA1.
aPharmacologie Fondamentale et Clinique de la Douleur, Clermont Université, Université d’Auvergne, BP 10448, F-63000 Clermont-Ferrand, France
bU766, INSERM [National Institute of Health and Medical Research], F-63000 Clermont-Ferrand, France
cU870, IFR62, INSERM, Oullins, France
dUMR1235, INRA [National Institute for Agricultural Research], Oullins, France
eUniversité Lyon 1, Lyon, France
fUMR1019 Nutrition Humaine, INRA, CRNH Auvergne, F-63000 Clermont-Ferrand, France
gUMR1019 Nutrition Humaine, Clermont Université, Université d’Auvergne, F-63000 Clermont-Ferrand, France
hU766, CIC 501, INSERM, F-63001 Clermont-Ferrand, France
*Corresponding author. Address: Laboratoire de Pharmacologie Fondamentale et Clinique de la Douleur, 24 place Henri Dunant, F-63000 Clermont-Ferrand, France. Tel.: +33 473 178 230; fax: +33 473 274 621.
1These authors contributed equally to this work.
Submitted July 27, 2011; revised and accepted November 16, 2011.