• Romina Nassini, Maarten Gees, Selena Harrison, Gaetano De Siena, Serena Materazzi, Nadia Moretto, Paola Failli, Delia Preti, Nicola Marchetti, Alberto Cavazzini, Francesca Mancini, Pamela Pedretti, Bernd Nilius, Riccardo Patacchini, and Pierangelo Geppetti.
• 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.
• Pain. 2011 Jul 1; 152 (7): 1621-1631.

AbstractPlatinum-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.Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

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