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Chronic pain is increasingly recognized as an important comorbidity of HI V-infected patients, however, the exact molecular mechanisms of HIV-related pain are still elusive. CCAAT/enhancer binding proteins (C/EBPs) are expressed in various tissues, including the CNS. C/EBPβ, one of the C/EBPs, is involved in the progression of HIV/A1DS, but the exact role of C/EBPjB and its upstream factors are not clear in HIV pain state. Here, we used a neuropathic pain model of perineural HIV envelope glycoprotein gp 120 application onto the rat sciatic nerve to test the role of phosphorylated C/EBPj3 (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gpl 20 induced overexpression of pC/EBPj8 in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPfS reduced mechanical allodynia. HIV gpl20 also increased TNFα, TNFRI, mitochondrial superoxide (mtO-2 ), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCRF.B enrichment on the C/EBPβ gene promoter regions in rats with g p l20 was higher than that in sham rats. Intrathecal TNF soluble receptor I (functionally blocking TNFα bioactivity) or knockdown of TNFRI using antisense oligodeoxynucleotide against TNFRI reduced mechanical allodynia, and decreased mtO-2 , pCREB and pC/EBPβ. Intrathecal Mito-tempol (a mitochondria-targetedO-2scavenger) reduced mechanical allodynia and decreased pCREB and pC/EBPβ. Knockdown of CREB with antisense oligodeoxynucleotide against CREB reduced mechanical allodynia and lowered pC/EBPβ. These results suggested that the pathway of TNFα/TNFRI-mtO-2 -pCREB triggers pC/EBP/J in the HIV gpl 20-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFα in vitro and repeated intrathecal injection of recombinant TNFα in naive rats. This finding provides new insights in the understanding of the HIV neuropathic pain mechanisms and treatment. [ABSTRACT FROM AUTHOR]