Pflügers Archiv - European Journal of Physiology

, Volume 463, Issue 4, pp 561–569

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
Ion Channels, Receptors and Transporters

DOI: 10.1007/s00424-011-1071-x

Cite this article as:
Materazzi, S., Fusi, C., Benemei, S. et al. Pflugers Arch - Eur J Physiol (2012) 463: 561. doi:10.1007/s00424-011-1071-x

Abstract

Paclitaxel produces a sensory neuropathy, characterized 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 completely by HC-030031 and in TRPA1-deficient mice. Exposure to paclitaxel of slices of mouse esophagus released the sensory neuropeptide, calcitonin gene-related peptide (CGRP). This effect was abolished by capsaicin desensitization 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 formation 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 

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Serena Materazzi
    • 1
  • Camilla Fusi
    • 1
  • Silvia Benemei
    • 1
  • Pamela Pedretti
    • 1
  • Riccardo Patacchini
    • 2
  • Bernd Nilius
    • 3
  • Jean Prenen
    • 3
  • Christophe Creminon
    • 4
  • Pierangelo Geppetti
    • 1
  • Romina Nassini
    • 1
  1. 1.Department of Preclinical and Clinical PharmacologyUniversity of FlorenceFlorenceItaly
  2. 2.Department of PharmacologyChiesi FarmaceuticiParmaItaly
  3. 3.Department of Molecular Cell BiologyKatholieke UniversiteitLeuvenBelgium
  4. 4.CEA, Institut de Biologie et Technologies de Saclay (iBiTec-S)Service de pharmacologie et d’immuno analyse (SPI)Gif sur YvetteFrance

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