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  • Our results on the other

    2022-06-22

    Our results, on the other hand, shows that there is no upregulation of ETBR on the spinal cord after SCI, but there is a significant difference of mRNA on days 2, 7 and 28 on the SCI group on the spinal cord and no changes on the DRG, suggesting that the spinal cord injury may reduce the renovation of this receptor in the tissue. This lower CP-673451 receptor of ETBR may result in the marked vasoconstriction observed after CNS trauma, as this receptor exerts a vasodilatory action [31]. Of particular interest is the finding that ETAR and ETBR protein expression was equally distributed in the spinal cord white matter through the different phases of recovery after SCI, however, in the grey matter, ETAR was upregulated on the 14th day post-SCI and no changes were observable on the grey matter for ETBR. Spinal cord injury leads to an extensive inflammatory cascade on spinal cord and the release of pro-inflammatory cytokines can sensitize neurons, activating signaling pathways that will result in thermal and mechanical hypersensitivity [39]. In this regard, Guo and collaborators (2014) demonstrated that the blockade of ETAR and ETBR significantly reduced the expression levels of TNF-α, IL-1β, IL-6 and iNOS, which could possibly influence the pain control exerted by the endothelin system. On that note, the involvement of ETAR on neuropathic pain after SCI seems more pronounced once we administrated inthratecally its peptide antagonist, BQ-123, indicating that there might be an interaction between endogenous ET-1 and ETAR on sensitization and this is in accordance to previous studies from our group that demonstrated that ETAR antagonist has reduced mechanical sensitivity in different nociceptive models [12], [40]. However, the antagonist of ETBR, BQ788, was unable to reduce mechanical sensitivity post-SCI. Even though ETBR has been related to inflammatory and central pain by the action of ET-1 [41], [42], [43], [44], we observe evidence that indicates that such responses post-SCI were mediated mainly by ETA receptors. Therefore, regarding the tactile responses after oral treatment of bosentan, blockade of ETAR/ETBR inhibited SCI-induced pain responses, suggesting once again the participation of endothelin receptors in bringing about these responses. Nevertheless, bosentan is already used in clinic for pulmonary arterial hypertension and is known to cross brain-blood barrier [45], [46]. Likewise, McKenzie and collaborators (1995) have demonstrated that the systemic administration of bosentan before SCI attenuated barrier breakdown along the axis of the spinal cord therefore demonstrating that endothelin has a role on modulation of barrier permeability after SCI. On that matter, it has been suggested that endothelin may contribute to this abnormal permeability through facilitation of secondary posttraumatic ischemia once there is a reduction in spinal cord blood flow at the impact site. It has been suggested that brain-spinal cord barrier disruption after SCI may even create an ideal opportunity for the influx of inflammatory mediators and proteins not usually permitted in the CNS. Conversely, this disruption provides a unique opportunity for therapeutic intervention [47].
    Conclusion In summary, we provided evidence that spinal cord injury animals do develop mechanical allodynia as well as an upregulation of mainly ETAR after spinal cord injury that are associated with the pain processing. Thus, endothelial receptors antagonists might constitute an attractive pharmacological tool for the treatment of neuropathic pain following SCI.
    Conflict of interest
    Acknowledgments This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Programa de Apoio aos Núcleos de Excelência (PRONEX) and by Fundação de Apoio a Pesquisa do Estado de Santa Catarina (FAPESC) (Brazil). S. Forner, A.C. Martini and E.L. de Andrade received a fellowship from CNPq.