ION CHANNELS, RECEPTORS AND TRANSPORTERS TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism Serena Materazzi & Camilla Fusi & Silvia Benemei & Pamela Pedretti & Riccardo Patacchini & Bernd Nilius & Jean Prenen & Christophe Creminon & Pierangelo Geppetti & Romina Nassini Received: 20 December 2011 / Accepted: 28 December 2011 / Published online: 19 January 2012 # Springer-Verlag 2012 Abstract Paclitaxel produces a sensory neuropathy, char- acterized by mechanical and cold hypersensitivity, which are abated by antioxidants. The transient receptor potential vanilloid 4 (TRPV4) channel has been reported to contribute to paclitaxel-evoked allodynia in rodents. We recently showed that TRP ankyrin 1 (TRPA1) channel mediates oxaliplatin-evoked cold and mechanical allodynia, and the drug targets TRPA1 via generation of oxidative stress. Here, we have explored whether TRPA1 activation contributes to paclitaxel-induced mechanical and cold hypersensitivity and whether this activation is mediated by oxidative stress generation. Paclitaxel-evoked mechanical allodynia was reduced partially by the TRPA1 antagonist, HC-030031, and the TRPV4 antagonist, HC-067047, and was completely abated by the combination of the two antagonists. The reduced paclitaxel-evoked mechanical allodynia, observed in TRPA1- deficient mice, was completely abolished when mice were treated with HC-067047. Cold allodynia was abated com- pletely by HC-030031 and in TRPA1-deficient mice. Ex- posure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitiza- tion and in calcium-free medium (indicating neurosecretion from sensory nerve terminals), partially reduced by either HC- 030031 or HC-067047, and completely abated in the presence of glutathione (GSH). Finally, the reduced CGRP release, observed in esophageal slices of TRPA1-deficient mice, was further inhibited by GSH. Paclitaxel via oxygen radical for- mation targets TRPA1 and TRPV4, and both channels are key for the delayed development of mechanical allodynia. Cold allodynia is, however, entirely dependent on TRPA1. Keywords Paclitaxel . TRPA1 . Cold and mechanical hyperalgesia . Primary sensory neurons . Oxidative stress Introduction Paclitaxel (Taxol) is a microtubule-targeting agent labeled for the treatment of a wide variety of solid neoplasms, including ovarian, breast and prostate cancer, currently under investiga- tion to assess its efficacy to treat additional malignant tumors. Peripheral neuropathy (PN) represents a dose-limiting adverse reaction, which negatively affects the quality of life of a relevant portion of patients and, importantly, results in therapy interruption or discontinuation [16]. As described by treated patients, PN by paclitaxel is characterized by various sensory symptoms including mechanical allody- nia, spontaneous pain, cold allodynia, ongoing burning pain, tingling, and numbness in a “stocking and glove” distri- bution [16]. Not infrequently, these symptoms do not resolve with the cessation of paclitaxel therapy and become chronic S. Materazzi : C. Fusi : S. Benemei : P. Pedretti : P. Geppetti (*) : R. Nassini Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy e-mail: pierangelo.geppetti@unifi.it R. Patacchini Department of Pharmacology, Chiesi Farmaceutici, Parma, Italy B. Nilius : J. Prenen Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium C. Creminon CEA, Institut de Biologie et Technologies de Saclay (iBiTec-S), Service de pharmacologie et d’immuno analyse (SPI), Gif sur Yvette, France Pflugers Arch - Eur J Physiol (2012) 463:561–569 DOI 10.1007/s00424-011-1071-x