title: Paclitaxel therapy potentiates cold hyperalgesia in streptozotocin-induced diabetic rats through enhanced mitochondrial reactive oxygen species production and TRPA1 sensitization.
abstract: 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.
authors.affiliation: Pharmacologie Fondamentale et Clinique de la Douleur, Clermont Université, Université d'Auvergne, BP 10448, F-63000 Clermont-Ferrand, France U766, INSERM [National Institute of Health and Medical Research], F-63000 Clermont-Ferrand, France U870, IFR62, INSERM, Oullins, France UMR1235, INRA [National Institute for Agricultural Research], Oullins, France Université Lyon 1, Lyon, France UMR1019 Nutrition Humaine, INRA, CRNH Auvergne, F-63000 Clermont-Ferrand, France UMR1019 Nutrition Humaine, Clermont Université, Université d'Auvergne, F-63000 Clermont-Ferrand, France U766, CIC 501, INSERM, F-63001 Clermont-Ferrand, France.
authors.forename: David André
authors.initials: DA
authors.lastname: Barrière
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rieusset
authors.forename: Didier
authors.initials: D
authors.lastname: Chanteranne
authors.forename: Jérôme
authors.initials: J
authors.lastname: Busserolles
authors.forename: Marie-Agnès
authors.initials: MA
authors.lastname: Chauvin
authors.forename: Laëtitia
authors.initials: L
authors.lastname: Chapuis
authors.forename: Jérôme
authors.initials: J
authors.lastname: Salles
authors.forename: Claude
authors.initials: C
authors.lastname: Dubray
authors.forename: Béatrice
authors.initials: B
authors.lastname: Morio
mesh_terms: D000111:Acetylcysteine / Q000627:therapeutic use; D000704:Analysis of Variance; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects*; D003080:Cold Temperature; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology; D005951:Glucose Tolerance Test; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000378:metabolism; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D007041:Hypoxanthine Phosphoribosyltransferase / Q000378:metabolism; D008297:Male; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D017239:Paclitaxel / Q000009:adverse effects*; D010147:Pain Measurement; D017288:Pain Threshold; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012584:Sciatic Nerve / Q000473:pathology; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000473:pathology / Q000648:ultrastructure; D013311:Streptozocin / Q000633:toxicity; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D017382:Reactive Oxygen Species; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; C480976:Trpa1 protein, rat; D013311:Streptozocin; D006861:Hydrogen Peroxide; D000080662:Phospholipid Hydroperoxide Glutathione Peroxidase; D005979:Glutathione Peroxidase; C523860:glutathione peroxidase 4, rat; D007041:Hypoxanthine Phosphoribosyltransferase; D017239:Paclitaxel; D000111:Acetylcysteine