Spinal CPEB-mtROS-CBP signaling pathway contributes to perineural HIV gp120 with ddC-related neuropathic pain in rats

Iida, Takafumi; Yi, Hyun; Li, Shue; Huang, Wan; Kanda, Hirotsugu; Lubarsky, David A.; Hao, Shuanglin

doi:10.1016/j.expneurol.2016.04.012

Cited by 31 publications

(26 citation statements)

References 81 publications

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“…1). Previous studies indicated that ddC administration also induce pain in young adult rats (Zheng et al, 2014; Iida et al, 2016). These results collectively indicate that pathogenesis of pain is a general side effect of the NRTI components in HAART.…”

Section: Discussionmentioning

confidence: 99%

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice

Yuan

Shi

Guo

et al. 2018

J Neuroimmune Pharmacol

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Highly Active Antiretroviral Therapy (HAART) has significantly contributed to the increase of HIV-infected survivors over 50 years of age. Unfortunately, patients are required to stay on long-term HAART, which may be causally related to the development of neurological problems such as chronic pain. Little is known about the contribution of HAART or its therapeutic agents to the pathogenesis of pain during aging. In this study, we determined the effect of nucleoside reverse transcriptase inhibitors (NRTIs) on the development of mechanical allodynia and the potential underlying mechanism in aging mice (15.5 months). We found that systemic administration of individual NRTIs, including ddC (2'-3'-dideoxycytidine), ddI (didanosine), AZT (3'-azido-3'-deoxythymidine) and d4T (2', 3'-didehydro-2', 3'-dideoxythymidine), induced allodynia in similar magnitudes and temporal profiles. We used ddC as a representative to investigate cellular and molecular processes induced by NRTIs in the spinal cord that probably underlie the development of allodynia. The results showed that ddC caused evident neuroinflammation in the spinal cord, suggested by the up-regulation of proinflammatory cytokines TNF-α and IL-1β and the reactions of microglia and astrocytes. In addition, we found that Wnt5a, a critical regulator of neuroinflammation, was also up-regulated. Pharmacological inhibition of Wnt5a blocked ddC-induced up-regulation of TNF-α and astrocyte reaction, while activation of Wnt5a signaling potentiated these processes. Furthermore, our data showed that inhibition of Wnt5a significantly reversed ddC-induced mechanical allodynia in aging mice. The results collectively suggest that NRTIs may contribute to the development of chronic pain in aging patients by inducing Wnt5a-regulated neuroinflammation.

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Section: Discussionmentioning

confidence: 99%

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice

Yuan

Shi

Guo

et al. 2018

J Neuroimmune Pharmacol

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“…In the absence of a response at a pressure of 15.1 g, animals were assigned to this cutoff value. Mechanical withdrawal threshold was determined according to the method described previously with a tactile stimulus producing a 50% likelihood of withdrawal determined by using the up-and-down method (Chaplan et al, 1994;Iida et al, 2016). Experimenters were blind to the group treatment during behavioral test.…”

Section: Methodsmentioning

confidence: 99%

“…ROS accumulation has been observed in the mitochondria of the SCDH neurons in a number of pain models (Schwartz et al, 2009;Kim et al, 2011;Salvemini et al, 2011;Kanao et al, 2015;Iida et al, 2016). mtROS interrelates with signaling events in the pathogenesis of chronic pain (Sui et al, 2013).…”

Section: Peripheral Gp120 Induced the Expression Of Tnf␣ Tnfri And mentioning

confidence: 99%

“…Reactive oxygen species (ROS) accumulation has been observed in the mitochondria of the SCDH neurons in different pain models (Schwartz et al, 2009;Kim et al, 2011;Salvemini et al, 2011). Mitochondrial ROS (mtROS) signaling events play an important role in the pathogenesis of chronic pain (Sui et al, 2013) and HIV pain model in rats (Kanao et al, 2015;Iida et al, 2016). The induction of cAMP response element binding protein (CREB) phosphorylation in spinal cord slices is in response to C-fiber stimulation, which mediates transcriptional regulation in the dorsal horn neurons (Kawasaki et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Phosphorylated CCAAT/Enhancer Binding Protein β Contributes to Rat HIV-Related Neuropathic Pain:In VitroandIn VivoStudies

Kashiwagi

et al. 2017

J. Neurosci.

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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 Oscavenger) 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.

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“…All drugs were dissolved in physiologic (0.9%) saline. The sample size estimate was based on our previous studies 16, 27 . The statistical significance of the differences was determined by one-way ANOVA (SPSS21, IBM, Armonk, NY, or StatView5, SAS Institute Inc.…”

Section: Drugs and Data Analysismentioning

confidence: 99%

Sirt3 mediated by lentiviral vector in the periaqueductal gray suppresses morphine withdrawal in rats: A preliminary study

et al. 2019

Preprint

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Opioid use disorder (OUD) is a significant clinical and social problem, inducing dependence/addiction and over-dose death. Opioid dependence/withdrawal contributes to the addiction vulnerability. Limited understanding of the exact mechanisms of morphine withdrawal leads to failure to adequately manage opioid withdrawal symptoms. Determining new molecular mechanisms of morphine withdrawal (MW) may allow development of novel therapeutic strategies for treating this disorder. Chronic morphine with naloxone precipitation induces MW behavioral response. Sirt3 (one member of sirtuins family) as a mitochondrial fidelity, plays an important role in mitochondrial homeostasis through the direct regulation of mitochondrial energy metabolism, ATP synthesis, detoxification of mitochondrial ROS, etc. In the pilot study, we found that (1) cultured neurons infected with lentiviral vector expressing Sirt3 induced over-expression of Sirt3, (2) microinjection of LV-Sirt3 into the vlPAG increased Sirt3 protein expression in rats, (3) MW lowered the expression of Sirt3 in the vlPAG, and (4) microinjection of LV-Sirt3 into the vlPAG decreased the MW behavioral response. Current preliminary study demonstrates that complement of Sirt3 in the PAG suppressed MW, providing a novel therapeutic approach to morphine physical withdrawal symptoms. The exact up-and/or down-stream factors of Sirt3 in the model are under the investigation.

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Spinal CPEB-mtROS-CBP signaling pathway contributes to perineural HIV gp120 with ddC-related neuropathic pain in rats

Cited by 31 publications

References 81 publications

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Induce Pathological Pain through Wnt5a-Mediated Neuroinflammation in Aging Mice

Phosphorylated CCAAT/Enhancer Binding Protein β Contributes to Rat HIV-Related Neuropathic Pain:In VitroandIn VivoStudies

Sirt3 mediated by lentiviral vector in the periaqueductal gray suppresses morphine withdrawal in rats: A preliminary study

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