Involvement of Endothelin Receptors in Peripheral Sensory Neuropathy Induced by Oxaliplatin in Mice
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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.
KeywordsPain Neuropathic pain Oxaliplatin Endothelin receptors
Endothelin ETA receptor antagonist
Endothelin ETB receptor antagonist
Dorsal root ganglia
Endothelin ETA receptor
Endothelin ETB receptor
Oxaliplatin-induced peripheral sensory neuropathy
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.
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.
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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