Neurotoxicity Research

, Volume 36, Issue 4, pp 688–699 | Cite as

Involvement of Endothelin Receptors in Peripheral Sensory Neuropathy Induced by Oxaliplatin in Mice

  • Renata Bessa Pontes
  • Mario Roberto Pontes Lisboa
  • Anamaria Falcão Pereira
  • Juliana Arcanjo Lino
  • Francisco Fábio Bezerra de Oliveira
  • Aline Kelly Viana de Mesquita
  • Bruno Wesley de Freitas Alves
  • Roberto César Pereira Lima-Júnior
  • Mariana Lima ValeEmail author
Original Article


The aim of this study was to evaluate the participation of the endothelin ETA and ETB receptors and the effects of bosentan in oxaliplatin-induced peripheral sensory neuropathy (OIN) in mice. Adult male Swiss mice received 1 mg/kg of oxaliplatin intravenously, twice a week for 5 weeks. Dorsal root ganglia (DRG) and spinal cords were removed for evaluation of the endothelin ETA and ETB receptor expression. Afterwards, selective (BQ-123 and BQ-788; 10 nmol in 30 μL, intraplantarly) and non-selective (bosentan, 100 mg/kg, orally) antagonists were administered in order to evaluate the involvement of the endothelin receptors in OIN. Mechanical and thermal nociception tests were performed once a week for 56 days. Oxaliplatin induced mechanical and thermal hypersensitivity and increased the endothelin ETA receptor expression in both the DRG and spinal cord (P < 0.05). Endothelin ETB receptor expression was increased in the DRG (P < 0.05) but not in the spinal cord. Both endothelin ETA and ETB receptor selective antagonists partially prevented mechanical hyperalgesia in mice with OIN (P < 0.05). Moreover, bosentan prevented mechanical and thermal hypersensitivity in oxaliplatin-treated mice (P < 0.05). In conclusion, both endothelin ETA and ETB receptors seem to be involved in the OIN in mice and they should be considered possible targets for the management of this clinical feature.


Pain Neuropathic pain Oxaliplatin Endothelin receptors 



Endothelin ETA receptor antagonist


Endothelin ETB receptor antagonist




Dorsal root ganglia




Endothelin ETA receptor


Endothelin ETB receptor


Glutamine synthetase


Oxaliplatin-induced peripheral sensory neuropathy






Spinal cord



The authors thank Maria Silvandira França Pinheiro, from the Department of Physiology and Pharmacology (Federal University of Ceará, Brazil), for the technical assistance, Dr. Ronaldo de Albuquerque Ribeiro (in memoriam) for his contribution to the development of this work, and the Multi-User Facility of Drug Research and Development Center of the Federal University of Ceará for the technical support.

Funding Information

The study was supported by the National Council for Scientific and Technological Development (CNPq) and the Foundation for Support in Scientific and Technological Development of Ceará (FUNCAP) (Process PR2-0101-00054.01.00/15).

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution at which the studies were conducted (protocol number 75/2012).


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Renata Bessa Pontes
    • 1
  • Mario Roberto Pontes Lisboa
    • 2
  • Anamaria Falcão Pereira
    • 3
  • Juliana Arcanjo Lino
    • 4
  • Francisco Fábio Bezerra de Oliveira
    • 3
  • Aline Kelly Viana de Mesquita
    • 1
  • Bruno Wesley de Freitas Alves
    • 2
  • Roberto César Pereira Lima-Júnior
    • 3
  • Mariana Lima Vale
    • 2
    • 3
    Email author
  1. 1.Department of Physical Therapy, Faculty of MedicineFederal University of CearáFortalezaBrazil
  2. 2.Department of Morphology, Faculty of MedicineFederal University of CearáFortalezaBrazil
  3. 3.Department of Physiology and Pharmacology, Faculty of MedicineFederal University of Ceará (UFC)FortalezaBrazil
  4. 4.Department of Clinical Medicine, Faculty of MedicineFederal University of CearáFortalezaBrazil

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