As expected, inflammatory factors and mediators, such as interleukins, cyclooxygenase 2, calcitonin gene-related peptide, tumor necrosis factor-α, were involved in the occurrence and development of pain.29–31 In our study, through functional enrichment analysis, we found that IL22RA1 connected with neuropathic pain after SCI. IL22RA1 was a unique receptor of IL-22.32 IL-22 was an IL-10 family cytokine generated by Th17, Th22, and Th1 cells, and IL-22 played an significant role in T cell-mediated inflammatory diseases.33IL22RA1 and its associated genes through cytoscape analyzing, including IFNA21 and IFNA2, mainly related to inflammation reaction in the GO-BP database. They may be the key genes of initiating the inflammatory response. Through MCODE analysis, we found that mir-6838-5p which may be the core of the module. Mir-6838-5p was associated with genetic RPS6KB1. The studies had shown that RPS6KB1 was closely related to the inflammatory and immune response.34,35Mir-6838-5p together with its targeted genes, such as NUP50, SSU72, and USP42, were closely associated with protein modification and biosynthesis through GO-BP database analysis. Therefore, we argued that IL22RA1 and mir-6838-5p played a vital role as inflammation reaction mediators in neuropathic pain induced by SCI.
In conclusion, FDZ1 could regulate the differentiation of neural stem cells into neurons and induce astrocyte proliferation. An important supporter of neuron cells, astrocytes can generate inflammatory mediators and mediate central sensitization of pain.36,37 Numerous researches suggest that astrocytes have also played a key role in immunoreaction.38–40 As a member of the IL-10 family, IL-22 has an effect in the inflammatory response. Mir-6838-5p could induce an immunoreaction through immunoregulation. Hence, we argue that astrocytes can be activated, releasing inflammatory mediators or immunomodulatory factor when the spinal cord is injured, inducing inflammation or immune response, resulting in central sensitization of acute pain and then producing chronic pain. Downregulation of FDZ1 would inhibit astrocytes activation, inflammatory medium (IL22) release and some genes expression (mir-6838-5p, IL22RA1). Thus, it may stop acute pain to translate into chronic pain. This would be beneficial for the treatment of intractable neuropathic pain induced by SCI.
Nevertheless, the currently popular molecules such as mitogen-activated protein kinase and nuclear factor kappa beta, are all involved in the formation and development of inflammation response pain or neuropathic pain.41–44 But in our study, these genes were not being filtered, it did not mean these signaling molecules or pathways not participation in neuropathic pain after SCI, it maybe not in the core position in the development of developing the pain, or further studies are needed in the future.
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