br Conclusion In summary we provided evidence that spinal co

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.
Introduction Endothelin (ET) is a short peptide found in vascular epithelial CRT 0066101 by the group of Dr. Yanagisawa and Dr. Masaki more than 10 years ago (Yanagisawa et al., 1988). It has very potent vasoconstricting effects and was originally thought to be involved in circulatory regulation. However, many other aspects of the pathophysiological role of ET have been uncovered since then (Kedzierski and Yanagisawa, 2001). There are three ETs, ET1, ET2 and ET3, and two closely related receptors, ETA and ETB, and their contribution in the development are extensively studied in gene knock out (KO) experiments. Both receptors mediate neuronal crest cell development and migration but differ in their site of action. In the case of ETA KO, the mice have craniofacial defects in which the lack of a jaw is the most obvious anomaly (Clouthier et al., 1998). Another phenotype is a strange aorta that is seen in half of the mice. ETA KO mice die soon after birth from asphyxia, because they cannot breath without jaws. In the case of ETB KO, developmental failure of epidermal melanocytes leads to colorless spotted skin and enteric neuron defect results in megacolon, because the GI tract can not undergo peristaltic movement to convey digested foods Hosoda et al., 1994, Shin et al., 1999. Since most of these transgenic animals were often lethal at shortly after birth, studies of the ET system after birth have been hampered. We have attempted to investigate the function of the ET system, employing highly specific antagonists to avoid the drawbacks in the gene knockout model such as lethality, adaptation/compensation and so on. We employed newly developed antagonists, specific for endothelin ETA receptor, to test whether this drug could mimic the phenotype with corresponding gene KO mice. And we have investigated physiological function of ETA in the post natal period when the ETA KO mice would die from asphyxia.
Results and Discussion
Conclusion What we have shown here is that highly specific antagonist can be a very useful tool, can mimic gene KO experiments or even further dissect receptor function. We just took ETA antagonist as an example and found that ETA mediates physiological closure of DA which would not be observed because of the immediate lethality in the gene KO experiments. And finally, we showed potential utilities of the ETA specific antagonists in tocolysis with NSAIDs.