Phosphorylated CCAAT/Enhancer Binding Protein ? Contributes to Rat HIV-Related Neuropathic Pain: In Vitro and In Vivo Studies.

ABSTRACT: Chronic pain is increasingly recognized as an important comorbidity of HIV-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/EBP?, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBP? and its upstream factors are not clear in HIV pain state. Here, we used a neuropathic pain model of perineural HIV envelope glycoprotein gp120 application onto the rat sciatic nerve to test the role of phosphorylated C/EBP? (pC/EBP?) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBP? in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBP? using siRNA against C/EBP? reduced mechanical allodynia. HIV gp120 also increased TNF?, TNFRI, mitochondrial superoxide (mtO2·-), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBP? gene promoter regions in rats with gp120 was higher than that in sham rats. Intrathecal TNF soluble receptor I (functionally blocking TNF? bioactivity) or knockdown of TNFRI using antisense oligodeoxynucleotide against TNFRI reduced mechanical allodynia, and decreased mtO2·-, pCREB and pC/EBP?. Intrathecal Mito-tempol (a mitochondria-targeted O2·-scavenger) reduced mechanical allodynia and decreased pCREB and pC/EBP?. Knockdown of CREB with antisense oligodeoxynucleotide against CREB reduced mechanical allodynia and lowered pC/EBP?. These results suggested that the pathway of TNF?/TNFRI-mtO2·--pCREB triggers pC/EBP? in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNF? in vitro and repeated intrathecal injection of recombinant TNF? in naive rats. This finding provides new insights in the understanding of the HIV neuropathic pain mechanisms and treatment.SIGNIFICANCE STATEMENT Painful HIV-associated sensory neuropathy is a neurological complication of HIV infection. Phosphorylated C/EBP? (pC/EBP?) influences AIDS progression, but it is still not clear about the exact role of pC/EBP? and the detailed upstream factors of pC/EBP? in HIV-related pain. In a neuropathic pain model of perineural HIV gp120 application onto the sciatic nerve, we found that pC/EBP? was triggered by TNF?/TNFRI-mtO2·--pCREB signaling pathway. The pathway was confirmed by using cultured neurons treated with recombinant TNF? in vitro, and by repeated intrathecal injection of recombinant TNF? in naive rats. The present results revealed the functional significance of TNF?/TNFRI-mtO2·--pCREB-pC/EBP? signaling in HIV neuropathic pain, and should help in the development of more specific treatments for neuropathic pain.

SUBMITTER: Yi H 

PROVIDER: S-EPMC5777110 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature