Skip to main content
SpringerLink
Log in

TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism

  • Ion Channels, Receptors and Transporters
  • Published:
Pflügers Archiv - European Journal of Physiology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Alessandri-Haber N, Dina OA, Joseph EK, Reichling DB, Levine JD (2008) Interaction of transient receptor potential vanilloid 4, integrin, and SRC tyrosine kinase in mechanical hyperalgesia. J Neurosci 28:1046–1057

    Article  PubMed  CAS  Google Scholar 

  2. Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD (2004) Transient receptor potential vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 24:4444–4452

    Article  PubMed  CAS  Google Scholar 

  3. Alexandre J, Batteux F, Nicco C, Chereau C, Laurent A, Guillevin L, Weill B, Goldwasser F (2006) Accumulation of hydrogen peroxide is an early and crucial step for paclitaxel-induced cancer cell death both in vitro and in vivo. Int J Cancer 119:41–48

    Article  PubMed  CAS  Google Scholar 

  4. Alexandre J, Hu Y, Lu W, Pelicano H, Huang P (2007) Novel action of paclitaxel against cancer cells: bystander effect mediated by reactive oxygen species. Cancer Res 67:3512–3517

    Article  PubMed  CAS  Google Scholar 

  5. Andersson DA, Gentry C, Moss S, Bevan S (2008) Transient receptor potential A1 is a sensory receptor for multiple products of oxidative stress. J Neurosci 28:2485–2494

    Article  PubMed  CAS  Google Scholar 

  6. Andre E, Campi B, Materazzi S, Trevisani M, Amadesi S, Massi D, Creminon C, Vaksman N, Nassini R, Civelli M, Baraldi PG, Poole DP, Bunnett NW, Geppetti P, Patacchini R (2008) Cigarette smoke-induced neurogenic inflammation is mediated by alpha, beta-unsaturated aldehydes and the TRPA1 receptor in rodents. J Clin Invest 118:2574–2582

    PubMed  CAS  Google Scholar 

  7. Bai J-Z, Lipski J (2010) Differential expression of TRPM2 and TRPV4 channels and their potential role in oxidative stress-induced cell death in organotypic hippocampal culture. Neurotoxicology 31:204–214

    Article  PubMed  CAS  Google Scholar 

  8. Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284

    Article  PubMed  CAS  Google Scholar 

  9. Bautista DM, Jordt SE, Nikai T, Tsuruda PR, Read AJ, Poblete J, Yamoah EN, Basbaum AI, Julius D (2006) TRPA1 mediates the inflammatory actions of environmental irritants and proalgesic agents. Cell 124:1269–1282

    Article  PubMed  CAS  Google Scholar 

  10. Bessac BF, Jordt SE (2010) Sensory detection and responses to toxic gases: mechanisms, health effects, and countermeasures. Proc Am Thorac Soc 7:269–277

    Article  PubMed  CAS  Google Scholar 

  11. Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE (2008) TRPA1 is a major oxidant sensor in murine airway sensory neurons. J Clin Invest 118:1899–1910

    Article  PubMed  CAS  Google Scholar 

  12. Cella D, Peterman A, Hudgens S, Webster K, Socinski MA (2003) Measuring the side effects of taxane therapy in oncology: the functional assessment of cancer therapy-taxane (FACT-taxane). Cancer 98:822–831

    Article  PubMed  CAS  Google Scholar 

  13. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63

    Article  PubMed  CAS  Google Scholar 

  14. Chen Y, Yang C, Wang ZJ (2011) Proteinase-activated receptor 2 sensitizes transient receptor potential vanilloid 1, transient receptor potential vanilloid 4, and transient receptor potential ankyrin 1 in paclitaxel-induced neuropathic pain. Neuroscience 193:440–451

    Article  PubMed  CAS  Google Scholar 

  15. Dai Y, Wang S, Tominaga M, Yamamoto S, Fukuoka T, Higashi T, Kobayashi K, Obata K, Yamanaka H, Noguchi K (2007) Sensitization of TRPA1 by PAR2 contributes to the sensation of inflammatory pain. J Clin Invest 117:1979–1987

    Article  PubMed  CAS  Google Scholar 

  16. Dougherty PM, Cata JP, Cordella JV, Burton A, Weng HR (2004) Taxol-induced sensory disturbance is characterized by preferential impairment of myelinated fiber function in cancer patients. Pain 109:132–142

    Article  PubMed  CAS  Google Scholar 

  17. Eid SR, Crown ED, Moore EL, Liang HA, Choong KC, Dima S, Henze DA, Kane SA, Urban MO (2008) HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity. Mol Pain 4:48–58

    Article  PubMed  Google Scholar 

  18. Everaerts W, Zhen X, Ghosh D, Vriens J, Gevaert T, Gilbert JP, Hayward NJ, McNamara CR, Xue F, Moran MM, Strassmaier T, Uykal E, Owsianik G, Vennekens R, De Ridder D, Nilius B, Fanger CM, Voets T (2010) Inhibition of the cation channel TRPV4 improves bladder function in mice and rats with cyclophosphamide-induced cystitis. Proc Natl Acad Sci USA 107:19084–19089

    Article  PubMed  CAS  Google Scholar 

  19. Flatters SJ, Bennett GJ (2004) Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral neuropathy. Pain 109:150–161

    Article  PubMed  CAS  Google Scholar 

  20. Flatters SJ, Xiao WH, Bennett GJ (2006) Acetyl-L-carnitine prevents and reduces paclitaxel-induced painful peripheral neuropathy. Neurosci Lett 397:219–223

    Article  PubMed  CAS  Google Scholar 

  21. Fukui M, Yamabe N, Zhu BT (2010) Resveratrol attenuates the anticancer efficacy of paclitaxel in human breast cancer cells in vitro and in vivo. Eur J Cancer 46:1882–1891

    Article  PubMed  CAS  Google Scholar 

  22. Gauchan P, Andoh T, Kato A, Kuraishi Y (2009) Involvement of increased expression of transient receptor potential melastatin 8 in oxaliplatin-induced cold allodynia in mice. Neurosci Lett 458:93–95

    Article  PubMed  CAS  Google Scholar 

  23. Geppetti P, Holzer P (1996) Neurogenic inflammation. CRC, Boca Raton

    Google Scholar 

  24. Grant AD, Cottrell GS, Amadesi S, Trevisani M, Nicoletti P, Materazzi S, Altier C, Cenac N, Zamponi GW, Bautista-Cruz F, Lopez CB, Joseph EK, Levine JD, Liedtke W, Vanner S, Vergnolle N, Geppetti P, Bunnett NW (2007) Protease-activated receptor 2 sensitizes the transient receptor potential vanilloid 4 ion channel to cause mechanical hyperalgesia in mice. J Physiol 578:715–733

    Article  PubMed  CAS  Google Scholar 

  25. Hadzic T, Aykin-Burns N, Zhu Y, Coleman MC, Leick K, Jacobson GM, Spitz DR (2010) Paclitaxel combined with inhibitors of glucose and hydroperoxide metabolism enhances breast cancer cell killing via H2O2-mediated oxidative stress. Free Radic Biol Med 48:1024–1033

    Article  PubMed  CAS  Google Scholar 

  26. Harrison S, Geppetti P (2001) Substance p. Int J Biochem Cell Biol 33:555–576

    Article  PubMed  CAS  Google Scholar 

  27. Itoh Y, Sendo T, Hirakawa T, Goromaru T, Takasaki S, Yahata H, Nakano H, Oishi R (2004) Role of sensory nerve peptides rather than mast cell histamine in paclitaxel hypersensitivity. Am J Respir Crit Care Med 169:113–119

    Article  PubMed  Google Scholar 

  28. Jordt SE, Bautista DM, Chuang HH, McKemy DD, Zygmunt PM, Hogestatt ED, Meng ID, Julius D (2004) Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 427:260–265

    Article  PubMed  CAS  Google Scholar 

  29. Liedtke W, Choe Y, Marti-Renom MA, Bell AM, Denis CS, Sali A, Hudspeth AJ, Friedman JM, Heller S (2000) Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell 103:525–535

    Article  PubMed  CAS  Google Scholar 

  30. Lyle PA, Mitsopoulos P, Suntres ZE (2011) N-acetylcysteine modulates the cytotoxic effects of paclitaxel. Chemotherapy 57:298–304

    Article  PubMed  CAS  Google Scholar 

  31. Materazzi S, Nassini R, Andre E, Campi B, Amadesi S, Trevisani M, Bunnett NW, Patacchini R, Geppetti P (2008) Cox-dependent fatty acid metabolites cause pain through activation of the irritant receptor TRPA1. Proc Natl Acad Sci USA 105:12045–12050

    Article  PubMed  CAS  Google Scholar 

  32. McNamara CR, Mandel-Brehm J, Bautista DM, Siemens J, Deranian KL, Zhao M, Hayward NJ, Chong JA, Julius D, Moran MM, Fanger CM (2007) TRPA1 mediates formalin-induced pain. Proc Natl Acad Sci USA 104:13525–13530

    Article  PubMed  CAS  Google Scholar 

  33. Miyano K, Tang HB, Nakamura Y, Morioka N, Inoue A, Nakata Y (2009) Paclitaxel and vinorelbine, evoked the release of substance P from cultured rat dorsal root ganglion cells through different PKC isoform-sensitive ion channels. Neuropharmacology 57:25–32

    Article  PubMed  CAS  Google Scholar 

  34. Nassini R, Gees M, Harrison S, De Siena G, Materazzi S, Moretto N, Failli P, Preti D, Marchetti N, Cavazzini A, Mancini F, Pedretti P, Nilius B, Patacchini R, Geppetti P (2011) Oxaliplatin elicits mechanical and cold allodynia in rodents via TRPA1 receptor. Pain 152:1621–1631

    Article  PubMed  CAS  Google Scholar 

  35. Nilius B, Owsianik G, Voets T, Peters JA (2007) Transient receptor potential cation channels in disease. Physiol Rev 87:165–217

    Article  PubMed  CAS  Google Scholar 

  36. Nilius B, Voets T (2007) Neurophysiology: channelling cold reception. Nature 448:147–148

    Article  PubMed  CAS  Google Scholar 

  37. Panis C, Herrera AC, Victorino VJ, Campos FC, Freitas LF, De Rossi T, Colado Simao AN, Cecchini AL, Cecchini R (2011) Oxidative stress and hematological profiles of advanced breast cancer patients subjected to paclitaxel or doxorubicin chemotherapy. Breast Cancer Res Treat. doi:10.1007/s10549-011-1693-x

  38. Ramanathan B, Jan KY, Chen CH, Hour TC, Yu HJ, Pu YS (2005) Resistance to paclitaxel is proportional to cellular total antioxidant capacity. Cancer Res 65:8455–8460

    Article  PubMed  CAS  Google Scholar 

  39. Rigas B, Sun Y (2008) Induction of oxidative stress as a mechanism of action of chemopreventive agents against cancer. Br J Cancer 98:1157–1160

    Article  PubMed  CAS  Google Scholar 

  40. Tatsushima Y, Egashira N, Kawashiri T, Mihara Y, Yano T, Mishima K, Oishi R (2011) Involvement of substance P in peripheral neuropathy induced by paclitaxel but not oxaliplatin. J Pharmacol Exp Ther 337:226–235

    Article  PubMed  CAS  Google Scholar 

  41. Trevisani M, Siemens J, Materazzi S, Bautista DM, Nassini R, Campi B, Imamachi N, Andre E, Patacchini R, Cottrell GS, Gatti R, Basbaum AI, Bunnett NW, Julius D, Geppetti P (2007) 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci USA 104:13519–13524

    Article  PubMed  CAS  Google Scholar 

  42. Trevisani M, Smart D, Gunthorpe MJ, Tognetto M, Barbieri M, Campi B, Amadesi S, Gray J, Jerman JC, Brough SJ, Owen D, Smith GD, Randall AD, Harrison S, Bianchi A, Davis JB, Geppetti P (2002) Ethanol elicits and potentiates nociceptor responses via the vanilloid receptor-1. Nat Neurosci 5:546–551

    Article  PubMed  CAS  Google Scholar 

  43. van den Bent MJ, van Raaij-van den, Aarssen VJ, Verweij J, Doorn PA, Sillevis Smitt PA (1997) Progression of paclitaxel-induced neuropathy following discontinuation of treatment. Muscle Nerve 20:750–752

    Article  PubMed  Google Scholar 

  44. Vergnolle N, Cenac N, Altier C, Cellars L, Chapman K, Zamponi GW, Materazzi S, Nassini R, Liedtke W, Cattaruzza F, Grady EF, Geppetti P, Bunnett NW (2010) A role for transient receptor potential vanilloid 4 in tonicity-induced neurogenic inflammation. Br J Pharmacol 159:1161–1173

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from Istituto Italiano di Tecnologia (Grant SEED, P.G.), Regione Toscana (Regional Health Research Program 2009, P.G.), and Ente Cassa Risparmio di Firenze.

Author information

Authors and Affiliations

  1. Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini 6, 50139, Florence, Italy

    Serena Materazzi, Camilla Fusi, Silvia Benemei, Pamela Pedretti, Pierangelo Geppetti & Romina Nassini

  2. Department of Pharmacology, Chiesi Farmaceutici, Parma, Italy

    Riccardo Patacchini

  3. Department of Molecular Cell Biology, Katholieke Universiteit, Leuven, Belgium

    Bernd Nilius & Jean Prenen

  4. CEA, Institut de Biologie et Technologies de Saclay (iBiTec-S), Service de pharmacologie et d’immuno analyse (SPI), Gif sur Yvette, France

    Christophe Creminon

Authors
  1. Serena Materazzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Camilla Fusi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silvia Benemei
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pamela Pedretti
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Riccardo Patacchini
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bernd Nilius
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jean Prenen
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Christophe Creminon
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Pierangelo Geppetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Romina Nassini
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Pierangelo Geppetti.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Materazzi, S., Fusi, C., Benemei, S. et al. TRPA1 and TRPV4 mediate paclitaxel-induced peripheral neuropathy in mice via a glutathione-sensitive mechanism. Pflugers Arch - Eur J Physiol 463, 561–569 (2012). https://doi.org/10.1007/s00424-011-1071-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00424-011-1071-x

Keywords

Search

Navigation