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    • Endothelins ETs are peptides expressed in both

    2021-07-27

    Endothelins (ETs) are peptides expressed in both the peripheral and the central nervous systems, which can contribute to sensory changes seen in animal models of inflammatory, cancer and neuropathic pain [10], [11]. All three mammalian isoforms (ET-1, ET-2 and ET-3) activate specific G protein-coupled endothelin type A (ETAR) and/or endothelin type B (ETBR) receptors. The ETAR shows higher affinity for ET-1 and ET-2 than ET-3 and is selectively blocked by several antagonists including BQ-123. The ETBR binds all three ET isoforms indiscriminately and is blocked by BQ-788 [12], [13]. Receptor binding studies in mammals, including humans demonstrated that endothelin receptors are distributed throughout the normal spinal cord [14], [15], [16]. Despite the evidence accumulated on the involvement of ETs and their receptors in many pain states, their potential contribution to nociception following SCI has not yet been investigated. Hence, the present study was designed to assess the roles exerted by ETAR and ETBR in neuropathic pain after SCI.
    Material and methods The experiments were carried out in male Wistar rats (270–300g) from Universidade Federal de Santa Catarina (Florianópolis, Brazil). All rats were housed under a normal day/night Florfenicol and with free access to food and water. Experiments were conducted in adherence to the Ethics Committee on Animal Use of the Universidade Federal de Santa Catarina (number PP00680) and NIH Guide for the Care and Use of Laboratory Animals.
    Results
    Discussion Spinal cord injury leads to important comorbidities, such as neuropathic pain. The current treatment options for neuropathic pain after SCI are still associated with moderate to ineffective responses followed by significant side effects in some patients [24], [25]. Following SCI, many secondary pathogenic events including ischemia, reactive gliosis and blood–spinal cord barrier breakdown, and such events are responsible to influence neuronal survival and regeneration. It has been suggested that endothelins are partially responsible for generating some of these events, with ETAR playing a prominent role in posttraumatic superoxide generation and disruption of the blood–spinal cord barrier, whereas ETBR is involved in mediating reactive gliosis [26], [27], [28], [29], [30]. On that matter, the endothelin family has been related to pain mechanisms and even though Peters and collaborators (2003) shown a higher distribution of ETAR instead of ETBR on the spinal cord, our study demonstrated similar expression levels on the naïve rats. Nevertheless, we have shown that there is an upregulation of ETAR on the spinal cord on the 21st day after SCI and this may be due to the high protein transcription of mRNA of ETA that is significantly higher on the SCI group starting on day 7 up to day 28 on the spinal cord. Interestingly, the mRNA of ETA on the DRG is only significantly higher on the 7th and 28th days after SCI, suggesting the participation of distinct cells on the DRG. It has been documented that ETAR are distributed on neurons and glial cells, as well as in vascular cells [32], [33], [34], [35] Therefore, the higher levels of ETA mRNA receptors on the spinal cord might suggest that this is due to the acute inflammatory and hemorrhage events after the trauma, as is related to subarachnoid hemorrhage and ischemia [36], [37]. On chronic stages after the spinal cord injury, we can suggest that there might be a higher expression of these receptors on the glial cells once there is the formation of the glial scar as well as the wallerian degeneration in accordance to a previous study that shows upregulation of ETAR in astrocytes after injuries in the CNS [38]. 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 expression 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.