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

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/EBPβ, one of the C/EBPs, is inv...

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Veröffentlicht in:The Journal of neuroscience 2018-01, Vol.38 (3), p.555-574
Hauptverfasser: Yi, Hyun, Liu, Shue, Kashiwagi, Yuta, Ikegami, Daigo, Huang, Wan, Kanda, Hirotsugu, Iida, Takafumi, Liu, Ching-Hang, Takahashi, Keiya, Lubarsky, David A, Hao, Shuanglin
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container_issue 3
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container_title The Journal of neuroscience
container_volume 38
creator Yi, Hyun
Liu, Shue
Kashiwagi, Yuta
Ikegami, Daigo
Huang, Wan
Kanda, Hirotsugu
Iida, Takafumi
Liu, Ching-Hang
Takahashi, Keiya
Lubarsky, David A
Hao, Shuanglin
description 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/EBPβ, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBPβ 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/EBPβ (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPβ in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPβ reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO ), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPβ gene promoter regions in rats with gp120 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 , pCREB and pC/EBPβ. Intrathecal Mito-tempol (a mitochondria-targeted O scavenger) 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 -pCREB triggers pC/EBPβ in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFα 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. Painful HIV-associated sensory neuropathy is a neurological complication of HIV infection. Phosphorylated C/EBPβ (pC/EBPβ) influences AIDS progression, but it is still not clear about the exact role of pC/EBPβ and the detailed upstream factors of pC/EBPβ in HIV-related pain. In a neuropathic pain model of perineural HIV gp120 application onto the sciatic nerve, we found that pC/EBPβ was triggered by TNFα/TNFRI-mtO -pCREB signaling pathway. The pathway was confirmed by using cultured neurons treated with recombinant TNFα , and by repeated int
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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/AIDS, but the exact role of C/EBPβ 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/EBPβ (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPβ in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPβ reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO ), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPβ gene promoter regions in rats with gp120 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 , pCREB and pC/EBPβ. Intrathecal Mito-tempol (a mitochondria-targeted O scavenger) 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 -pCREB triggers pC/EBPβ in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFα 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. Painful HIV-associated sensory neuropathy is a neurological complication of HIV infection. Phosphorylated C/EBPβ (pC/EBPβ) influences AIDS progression, but it is still not clear about the exact role of pC/EBPβ and the detailed upstream factors of pC/EBPβ in HIV-related pain. In a neuropathic pain model of perineural HIV gp120 application onto the sciatic nerve, we found that pC/EBPβ was triggered by TNFα/TNFRI-mtO -pCREB signaling pathway. The pathway was confirmed by using cultured neurons treated with recombinant TNFα , and by repeated intrathecal injection of recombinant TNFα in naive rats. The present results revealed the functional significance of TNFα/TNFRI-mtO -pCREB-pC/EBPβ signaling in HIV neuropathic pain, and should help in the development of more specific treatments for neuropathic pain.</description><identifier>ISSN: 0270-6474</identifier><identifier>EISSN: 1529-2401</identifier><identifier>DOI: 10.1523/JNEUROSCI.3647-16.2017</identifier><identifier>PMID: 29196315</identifier><language>eng</language><publisher>United States: Society for Neuroscience</publisher><subject>Acquired immune deficiency syndrome ; AIDS ; Animals ; Antisense RNA ; Biological activity ; CCAAT-Enhancer-Binding Protein-beta - metabolism ; CCAAT/enhancer-binding protein ; Central nervous system ; Chronic pain ; Chronic Pain - metabolism ; Chronic Pain - virology ; Cyclic AMP response element-binding protein ; Cyclic AMP Response Element-Binding Protein - metabolism ; Dorsal horn ; Glycoprotein gp120 ; Glycoproteins ; HIV ; HIV Envelope Protein gp120 - pharmacology ; HIV Infections - complications ; Human immunodeficiency virus ; In vivo methods and tests ; Male ; Mitochondria ; Molecular modelling ; Neuralgia ; Neuralgia - metabolism ; Neuralgia - virology ; Pain ; Pain perception ; Proteins ; Rats ; Rats, Sprague-Dawley ; Sciatic nerve ; Signal Transduction - drug effects ; Signal Transduction - physiology ; siRNA ; Spinal cord ; Spinal Cord Dorsal Horn - drug effects ; Spinal Cord Dorsal Horn - metabolism ; Superoxide ; Superoxides - metabolism ; Tempol ; Tumor Necrosis Factor-alpha - metabolism ; Tumor necrosis factor-α</subject><ispartof>The Journal of neuroscience, 2018-01, Vol.38 (3), p.555-574</ispartof><rights>Copyright © 2018 the authors 0270-6474/18/380555-20$15.00/0.</rights><rights>Copyright Society for Neuroscience Jan 17, 2018</rights><rights>Copyright © 2018 the authors 0270-6474/18/380555-20$15.00/0 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c394t-e5dec402c7050ededbf54bf112e89f71374c89d5295a0f6f857b7a2652149c83</citedby><cites>FETCH-LOGICAL-c394t-e5dec402c7050ededbf54bf112e89f71374c89d5295a0f6f857b7a2652149c83</cites><orcidid>0000-0003-2435-1473 ; 0000-0002-7809-5789</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777110/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5777110/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29196315$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yi, Hyun</creatorcontrib><creatorcontrib>Liu, Shue</creatorcontrib><creatorcontrib>Kashiwagi, Yuta</creatorcontrib><creatorcontrib>Ikegami, Daigo</creatorcontrib><creatorcontrib>Huang, Wan</creatorcontrib><creatorcontrib>Kanda, Hirotsugu</creatorcontrib><creatorcontrib>Iida, Takafumi</creatorcontrib><creatorcontrib>Liu, Ching-Hang</creatorcontrib><creatorcontrib>Takahashi, Keiya</creatorcontrib><creatorcontrib>Lubarsky, David A</creatorcontrib><creatorcontrib>Hao, Shuanglin</creatorcontrib><title>Phosphorylated CCAAT/Enhancer Binding Protein β Contributes to Rat HIV-Related Neuropathic Pain: In Vitro and In Vivo Studies</title><title>The Journal of neuroscience</title><addtitle>J Neurosci</addtitle><description>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/EBPβ, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBPβ 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/EBPβ (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPβ in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPβ reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO ), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPβ gene promoter regions in rats with gp120 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 , pCREB and pC/EBPβ. Intrathecal Mito-tempol (a mitochondria-targeted O scavenger) 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 -pCREB triggers pC/EBPβ in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFα 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. Painful HIV-associated sensory neuropathy is a neurological complication of HIV infection. Phosphorylated C/EBPβ (pC/EBPβ) influences AIDS progression, but it is still not clear about the exact role of pC/EBPβ and the detailed upstream factors of pC/EBPβ in HIV-related pain. In a neuropathic pain model of perineural HIV gp120 application onto the sciatic nerve, we found that pC/EBPβ was triggered by TNFα/TNFRI-mtO -pCREB signaling pathway. The pathway was confirmed by using cultured neurons treated with recombinant TNFα , and by repeated intrathecal injection of recombinant TNFα in naive rats. The present results revealed the functional significance of TNFα/TNFRI-mtO -pCREB-pC/EBPβ signaling in HIV neuropathic pain, and should help in the development of more specific treatments for neuropathic pain.</description><subject>Acquired immune deficiency syndrome</subject><subject>AIDS</subject><subject>Animals</subject><subject>Antisense RNA</subject><subject>Biological activity</subject><subject>CCAAT-Enhancer-Binding Protein-beta - metabolism</subject><subject>CCAAT/enhancer-binding protein</subject><subject>Central nervous system</subject><subject>Chronic pain</subject><subject>Chronic Pain - metabolism</subject><subject>Chronic Pain - virology</subject><subject>Cyclic AMP response element-binding protein</subject><subject>Cyclic AMP Response Element-Binding Protein - metabolism</subject><subject>Dorsal horn</subject><subject>Glycoprotein gp120</subject><subject>Glycoproteins</subject><subject>HIV</subject><subject>HIV Envelope Protein gp120 - pharmacology</subject><subject>HIV Infections - complications</subject><subject>Human immunodeficiency virus</subject><subject>In vivo methods and tests</subject><subject>Male</subject><subject>Mitochondria</subject><subject>Molecular modelling</subject><subject>Neuralgia</subject><subject>Neuralgia - metabolism</subject><subject>Neuralgia - virology</subject><subject>Pain</subject><subject>Pain perception</subject><subject>Proteins</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Sciatic nerve</subject><subject>Signal Transduction - drug effects</subject><subject>Signal Transduction - physiology</subject><subject>siRNA</subject><subject>Spinal cord</subject><subject>Spinal Cord Dorsal Horn - drug effects</subject><subject>Spinal Cord Dorsal Horn - metabolism</subject><subject>Superoxide</subject><subject>Superoxides - metabolism</subject><subject>Tempol</subject><subject>Tumor Necrosis Factor-alpha - metabolism</subject><subject>Tumor necrosis factor-α</subject><issn>0270-6474</issn><issn>1529-2401</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkdFu2yAYhdG0ac3avUKFtJvdOAUMxuxiUmZla6aqjdK0twhjXFM5kAKu1Js91B5kzzRHaaNuV7_QOf_5OfoAOMVoihnJz35ezm9WV9fVYpoXlGe4mBKE-RswGVWREYrwWzBBhKNslOkR-BDjPUKIj6b34IgILIocswn4tex83HY-PPUqmQZW1Wy2Ppu7TjltAvxmXWPdHVwGn4x18M9vWHmXgq2HZCJMHq5UgueL22xl9gGXZgh-q1JnNVwq677AhYO3NgUPlWv2j0cPr9PQWBNPwLtW9dF8fJ7HYP19vq7Os4urH4tqdpHpXNCUGdYYTRHRHDFkGtPULaN1izExpWg5zjnVpWjG6kyhtmhLxmuuSMEIpkKX-TH4uo_dDvXGNNqMFVQvt8FuVHiSXln5r-JsJ-_8o2Scc4zRGPD5OSD4h8HEJDc2atP3yhk_RIkFx4XIc7a79ek_670fghvbSYIEpaLkZTG6ir1LBx9jMO3hMxjJHWF5ICx3hCUu5I7wuHj6usph7QVp_hf3WaQW</recordid><startdate>20180117</startdate><enddate>20180117</enddate><creator>Yi, Hyun</creator><creator>Liu, Shue</creator><creator>Kashiwagi, Yuta</creator><creator>Ikegami, Daigo</creator><creator>Huang, Wan</creator><creator>Kanda, Hirotsugu</creator><creator>Iida, Takafumi</creator><creator>Liu, Ching-Hang</creator><creator>Takahashi, Keiya</creator><creator>Lubarsky, David A</creator><creator>Hao, Shuanglin</creator><general>Society for Neuroscience</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QR</scope><scope>7TK</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0003-2435-1473</orcidid><orcidid>https://orcid.org/0000-0002-7809-5789</orcidid></search><sort><creationdate>20180117</creationdate><title>Phosphorylated CCAAT/Enhancer Binding Protein β Contributes to Rat HIV-Related Neuropathic Pain: In Vitro and In Vivo Studies</title><author>Yi, Hyun ; Liu, Shue ; Kashiwagi, Yuta ; Ikegami, Daigo ; Huang, Wan ; Kanda, Hirotsugu ; Iida, Takafumi ; Liu, Ching-Hang ; Takahashi, Keiya ; Lubarsky, David A ; Hao, Shuanglin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c394t-e5dec402c7050ededbf54bf112e89f71374c89d5295a0f6f857b7a2652149c83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Acquired immune deficiency syndrome</topic><topic>AIDS</topic><topic>Animals</topic><topic>Antisense RNA</topic><topic>Biological activity</topic><topic>CCAAT-Enhancer-Binding Protein-beta - metabolism</topic><topic>CCAAT/enhancer-binding protein</topic><topic>Central nervous system</topic><topic>Chronic pain</topic><topic>Chronic Pain - metabolism</topic><topic>Chronic Pain - virology</topic><topic>Cyclic AMP response element-binding protein</topic><topic>Cyclic AMP Response Element-Binding Protein - metabolism</topic><topic>Dorsal horn</topic><topic>Glycoprotein gp120</topic><topic>Glycoproteins</topic><topic>HIV</topic><topic>HIV Envelope Protein gp120 - pharmacology</topic><topic>HIV Infections - complications</topic><topic>Human immunodeficiency virus</topic><topic>In vivo methods and tests</topic><topic>Male</topic><topic>Mitochondria</topic><topic>Molecular modelling</topic><topic>Neuralgia</topic><topic>Neuralgia - metabolism</topic><topic>Neuralgia - virology</topic><topic>Pain</topic><topic>Pain perception</topic><topic>Proteins</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Sciatic nerve</topic><topic>Signal Transduction - drug effects</topic><topic>Signal Transduction - physiology</topic><topic>siRNA</topic><topic>Spinal cord</topic><topic>Spinal Cord Dorsal Horn - drug effects</topic><topic>Spinal Cord Dorsal Horn - metabolism</topic><topic>Superoxide</topic><topic>Superoxides - metabolism</topic><topic>Tempol</topic><topic>Tumor Necrosis Factor-alpha - metabolism</topic><topic>Tumor necrosis factor-α</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Yi, Hyun</creatorcontrib><creatorcontrib>Liu, Shue</creatorcontrib><creatorcontrib>Kashiwagi, Yuta</creatorcontrib><creatorcontrib>Ikegami, Daigo</creatorcontrib><creatorcontrib>Huang, Wan</creatorcontrib><creatorcontrib>Kanda, Hirotsugu</creatorcontrib><creatorcontrib>Iida, Takafumi</creatorcontrib><creatorcontrib>Liu, Ching-Hang</creatorcontrib><creatorcontrib>Takahashi, Keiya</creatorcontrib><creatorcontrib>Lubarsky, David A</creatorcontrib><creatorcontrib>Hao, Shuanglin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>The Journal of neuroscience</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yi, Hyun</au><au>Liu, Shue</au><au>Kashiwagi, Yuta</au><au>Ikegami, Daigo</au><au>Huang, Wan</au><au>Kanda, Hirotsugu</au><au>Iida, Takafumi</au><au>Liu, Ching-Hang</au><au>Takahashi, Keiya</au><au>Lubarsky, David A</au><au>Hao, Shuanglin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phosphorylated CCAAT/Enhancer Binding Protein β Contributes to Rat HIV-Related Neuropathic Pain: In Vitro and In Vivo Studies</atitle><jtitle>The Journal of neuroscience</jtitle><addtitle>J Neurosci</addtitle><date>2018-01-17</date><risdate>2018</risdate><volume>38</volume><issue>3</issue><spage>555</spage><epage>574</epage><pages>555-574</pages><issn>0270-6474</issn><eissn>1529-2401</eissn><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/EBPβ, one of the C/EBPs, is involved in the progression of HIV/AIDS, but the exact role of C/EBPβ 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/EBPβ (pC/EBPβ) and its upstream pathway in the spinal cord dorsal horn (SCDH). HIV gp120 induced overexpression of pC/EBPβ in the ipsilateral SCDH compared with contralateral SCDH. Inhibition of C/EBPβ using siRNA against C/EBPβ reduced mechanical allodynia. HIV gp120 also increased TNFα, TNFRI, mitochondrial superoxide (mtO ), and pCREB in the ipsilateral SCDH. ChIP-qPCR assay showed that pCREB enrichment on the C/EBPβ gene promoter regions in rats with gp120 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 , pCREB and pC/EBPβ. Intrathecal Mito-tempol (a mitochondria-targeted O scavenger) 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 -pCREB triggers pC/EBPβ in the HIV gp120-induced neuropathic pain state. Furthermore, we confirmed the pathway using both cultured neurons treated with recombinant TNFα 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. Painful HIV-associated sensory neuropathy is a neurological complication of HIV infection. Phosphorylated C/EBPβ (pC/EBPβ) influences AIDS progression, but it is still not clear about the exact role of pC/EBPβ and the detailed upstream factors of pC/EBPβ in HIV-related pain. In a neuropathic pain model of perineural HIV gp120 application onto the sciatic nerve, we found that pC/EBPβ was triggered by TNFα/TNFRI-mtO -pCREB signaling pathway. The pathway was confirmed by using cultured neurons treated with recombinant TNFα , and by repeated intrathecal injection of recombinant TNFα in naive rats. The present results revealed the functional significance of TNFα/TNFRI-mtO -pCREB-pC/EBPβ signaling in HIV neuropathic pain, and should help in the development of more specific treatments for neuropathic pain.</abstract><cop>United States</cop><pub>Society for Neuroscience</pub><pmid>29196315</pmid><doi>10.1523/JNEUROSCI.3647-16.2017</doi><tpages>20</tpages><orcidid>https://orcid.org/0000-0003-2435-1473</orcidid><orcidid>https://orcid.org/0000-0002-7809-5789</orcidid><oa>free_for_read</oa></addata></record>
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subjects Acquired immune deficiency syndrome
AIDS
Animals
Antisense RNA
Biological activity
CCAAT-Enhancer-Binding Protein-beta - metabolism
CCAAT/enhancer-binding protein
Central nervous system
Chronic pain
Chronic Pain - metabolism
Chronic Pain - virology
Cyclic AMP response element-binding protein
Cyclic AMP Response Element-Binding Protein - metabolism
Dorsal horn
Glycoprotein gp120
Glycoproteins
HIV
HIV Envelope Protein gp120 - pharmacology
HIV Infections - complications
Human immunodeficiency virus
In vivo methods and tests
Male
Mitochondria
Molecular modelling
Neuralgia
Neuralgia - metabolism
Neuralgia - virology
Pain
Pain perception
Proteins
Rats
Rats, Sprague-Dawley
Sciatic nerve
Signal Transduction - drug effects
Signal Transduction - physiology
siRNA
Spinal cord
Spinal Cord Dorsal Horn - drug effects
Spinal Cord Dorsal Horn - metabolism
Superoxide
Superoxides - metabolism
Tempol
Tumor Necrosis Factor-alpha - metabolism
Tumor necrosis factor-α
title Phosphorylated CCAAT/Enhancer Binding Protein β Contributes to Rat HIV-Related Neuropathic Pain: In Vitro and In Vivo Studies
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