title: Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor stimulation.
abstract: Platinum-based anticancer drugs cause neurotoxicity. In particular, oxaliplatin produces early-developing, painful, and cold-exacerbated paresthesias. However, the mechanism underlying these bothersome and dose-limiting adverse effects is unknown. We hypothesized that the transient receptor potential ankyrin 1 (TRPA1), a cation channel activated by oxidative stress and cold temperature, contributes to mechanical and cold hypersensitivity caused by oxaliplatin and cisplatin. Oxaliplatin and cisplatin evoked glutathione-sensitive relaxation, mediated by TRPA1 stimulation and the release of calcitonin gene-related peptide from sensory nerve terminals in isolated guinea pig pulmonary arteries. No calcium response was observed in cultured mouse dorsal root ganglion neurons or in naïve Chinese hamster ovary (CHO) cells exposed to oxaliplatin or cisplatin. However, oxaliplatin, and with lower potency, cisplatin, evoked a glutathione-sensitive calcium response in CHO cells expressing mouse TRPA1. One single administration of oxaliplatin produced mechanical and cold hyperalgesia in rats, an effect selectively abated by the TRPA1 antagonist HC-030031. Oxaliplatin administration caused mechanical and cold allodynia in mice. Both responses were absent in TRPA1-deficient mice. Administration of cisplatin evoked mechanical allodynia, an effect that was reduced in TRPA1-deficient mice. TRPA1 is therefore required for oxaliplatin-evoked mechanical and cold hypersensitivity, and contributes to cisplatin-evoked mechanical allodynia. Channel activation is most likely caused by glutathione-sensitive molecules, including reactive oxygen species and their byproducts, which are generated after tissue exposure to platinum-based drugs from cells surrounding nociceptive nerve terminals.
authors.affiliation: Department of Preclinical and Clinical Pharmacology, University of Florence, Florence, Italy Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium Department of Pharmacology, Chiesi Farmaceutici, Parma, Italy Department of Pharmaceutical Chemistry, University of Ferrara, Ferrara, Italy Chemistry Department, University of Ferrara, Ferrara, Italy.
authors.forename: Romina
authors.initials: R
authors.lastname: Nassini
authors.forename: Maarten
authors.initials: M
authors.lastname: Gees
authors.forename: Selena
authors.initials: S
authors.lastname: Harrison
authors.forename: Gaetano
authors.initials: G
authors.lastname: De Siena
authors.forename: Serena
authors.initials: S
authors.lastname: Materazzi
authors.forename: Nadia
authors.initials: N
authors.lastname: Moretto
authors.forename: Paola
authors.initials: P
authors.lastname: Failli
authors.forename: Delia
authors.initials: D
authors.lastname: Preti
authors.forename: Nicola
authors.initials: N
authors.lastname: Marchetti
authors.forename: Alberto
authors.initials: A
authors.lastname: Cavazzini
authors.forename: Francesca
authors.initials: F
authors.lastname: Mancini
authors.forename: Pamela
authors.initials: P
authors.lastname: Pedretti
authors.forename: Bernd
authors.initials: B
authors.lastname: Nilius
authors.forename: Riccardo
authors.initials: R
authors.lastname: Patacchini
authors.forename: Pierangelo
authors.initials: P
authors.lastname: Geppetti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001285:Atropine / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D002478:Cells, Cultured; D002851:Chromatography, High Pressure Liquid; D002945:Cisplatin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D004347:Drug Interactions; D005727:Ganglia, Spinal / Q000166:cytology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006168:Guinea Pigs; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009944:Organoplatinum Compounds / Q000633:toxicity*; D000077150:Oxaliplatin; D010147:Pain Measurement; D010879:Piperazines; D011651:Pulmonary Artery / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D011984:Sensory Receptor Cells / Q000187:drug effects; D021241:Spectrometry, Mass, Electrospray Ionization; D013481:Superoxides / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D046509:Tissue Culture Techniques; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D004151:Dipeptides; D009944:Organoplatinum Compounds; D010879:Piperazines; D011799:Quinazolines; D000074025:TRPA1 Cation Channel; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D000077150:Oxaliplatin; D013481:Superoxides; D001285:Atropine; D015740:Calcitonin Gene-Related Peptide; C071423:capsazepine; D002945:Cisplatin; D002211:Capsaicin; D002118:Calcium; C406305:olcegepant