Morphine Exacerbates HIV-1 Tat-Induced Cytokine Production in Astrocytes through Convergent Effects on [Ca2+]i, NF-κB Trafficking and Transcription

El‐Hage, Nazira; Bruce‐Keller, Annadora J.; Yakovleva, Tatiana; Bazov, Igor; Bakalkin, Georgy; Knapp, Pamela E.; Hauser, Kurt F.

doi:10.1371/journal.pone.0004093

Cited by 109 publications

(114 citation statements)

References 60 publications

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“…In the present study, Tat Ϯ morphine elevated CCL2/MCP-1, CCL5/RANTES, and IL-6 in vivo after 48 hours (Figure 3). This parallels our previous findings in vitro 24,27 and suggests enhanced inflammatory tone may contribute to dendrite pathology. From a therapeutic standpoint, it is important to recognize that synaptic apoptosis and focal losses in dendritic structure and function are not necessarily a prelude to death and in fact may be reversible.…”

Section: Structural Changes In Dendrites Induced By Hiv-1 Tat ϯ Morphinesupporting

confidence: 91%

“…24 -26 The present work was undertaken to extend previous results suggesting that HIV-1 Tat exposure might disrupt endogenous opioid and chemokine signaling. 10,24,27 Addi-tionally, we tested for subtle neuropathological changes that might be caused by HIV-1 Tat and opiate interactions since neuron death (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling) was not observed in our previous study. 14 Wild-type and transgenic mice expressing HIV-1 Tat 1-86 regulated by a doxycycline (DOX) inducible, glial fibrillary acidic protein (GFAP) promoter were continuously treated with placebo, morphine, and/or naltrexone (s.c. implants) Ϯ DOX for 2, 7, or 10 days.…”

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confidence: 99%

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Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Fitting

Bull

et al. 2010

The American Journal of Pathology

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HIV-1 infection predisposes the central nervous system to damage by opportunistic infections and environmental insults. Such maladaptive plasticity may underlie the exaggerated comorbidity seen with HIV-1 infection and opioid abuse. Although morphine and HIV-1 Tat synergize at high concentrations to increase neuronal death in vitro, we questioned whether chronic low Tat exposure in vivo might contribute to the spectrum of neuropathology through sublethal neuronal injury. We used a doxycycline-driven, inducible, HIV-1 Tat transgenic mouse, in which striatal neuron death was previously shown to be absent, to examine effects of differential Tat expression, alone and combined with morphine. Low constitutive Tat expression caused neurodegeneration; higher levels induced by 7 days of doxycycline significantly reduced dendritic spine numbers. Moreover, Tat expression widely disrupted the endogenous opioid system, altering and , but not ␦, opioid receptor and proopiomelanocortin, proenkephalin, and prodynorphin transcript levels in cortex, hippocampus, and striatum. In addition to markedly reducing spine density by itself, morphine amplified the effect of higher levels of Tat on spines, and also potentiated Tat-mediated dendritic pathology, thus contributing to maladaptive neuroplasticity at multiple levels. The dendritic pathology and reductions in spine density suggest that sustained Tat ؎ morphine exposure un- Exposure to HIV results in neurodegenerative alterations in the central nervous system (CNS) of a substantial proportion of patients, even in the era of highly active anti-retroviral therapy. Highly active anti-retroviral therapy does not readily cross the blood-brain barrier, making the CNS a safe-haven for infection, and permitting ongoing degenerative changes even when viral titers are quite low in the periphery. [1][2][3][4][5][6] There is considerable evidence, both in patients and in experimental models, that coexposure to abused opiate drugs can hasten the onset and worsen the outcome of HIV encephalitis and other neurodegenerative changes.7-15 A more limited number of studies show that opioids increase viral loads, and hasten disease progression and/or neuropathology in simian immunodeficiency models, 16 -19 although this has been controversial. 20 -22 Our in vitro work has consistently shown evidence for interactions between Tat or gp120 and morphine that accelerate neurodegeneration. These interactive effects appear to be orchestrated by glial cells, 23 and likely involve synergistic upregulation of proinflammatory chemokine/cytokine release and production of reactive species. 24 -26 The present work was undertaken to extend previous results suggesting that HIV-1 Tat exposure might disrupt endogenous opioid and chemokine signaling.

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Section: Structural Changes In Dendrites Induced By Hiv-1 Tat ϯ Morphinesupporting

confidence: 91%

mentioning

confidence: 99%

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Fitting

Bull

et al. 2010

The American Journal of Pathology

Self Cite

132

106

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“…Notably, NF-κB activation can also be modulated by G-protein-coupled receptors, such as the μ-opioid receptor, through a variety of upstream events including the cAMP/PKA/CREB, PI3K/Akt/IKK, and PLC/ PKC/IkK pathways [12,43] . Recent studies have shown that, in cultured astrocytes from mice, exposure to morphine plus HIV Tat is sufficient to activate NF-κB and cytokine production [44] . Based on a number of previous studies showing that NF-κB regulates the expression of TNF-α, IL-1β, and IL-6 in immune cells and investigating the effects of TNF-α and IL-1β on NF-κB activation in glial cells [45] , it has been postulated that a positive feedback loop exists between pro-inflammatory cytokine expression and NF-κB activation [11] .…”

Section: Discussionmentioning

confidence: 99%

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

et al. 2014

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Nuclear factor kappa B (NF-κB) in the spinal cord is involved in pro-infl ammatory cytokine-mediated pain facilitation. However, the role of NF-κB activation in chronic morphine-induced analgesic tolerance and the underlying mechanisms remain unclear. In the present study, we found that the level of phosphorylated NF-κB p65 (p-p65) was increased in the dorsal horn of the lumbar 4-6 segments after intrathecal administration of morphine for 7 consecutive days, and the p-p65 was co-localized with neurons and astrocytes. The expression of TNF-α and IL-1β was also increased in the same area. In addition, pretreatment with pyrrolidinedithiocarbamate (PDTC) or SN50, inhibitors of NF-κB, prevented the development of morphine analgesic tolerance and alleviated morphine withdrawal-induced allodynia and hyperalgesia. The increase in TNF-α and IL-1β expression induced by chronic morphine exposure was also partially blocked by PDTC pretreatment. In another experiment, rats receiving PDTC or SN50 beginning on day 7 of morphine injection showed partial recovery of the anti-nociceptive effects of morphine and attenuation of the withdrawal-induced abnormal pain. Meanwhile, intrathecal pretreatment with lipopolysaccharide from Rhodobacter sphae roides, an antagonist of toll-like receptor 4 (TLR4), blocked the activation of NF-κB, and prevented the development of morphine tolerance and withdrawalinduced abnormal pain. These data indicated that TLR4-mediated NF-κB activation in the spinal cord is involved in the development and maintenance of morphine analgesic tolerance and withdrawalinduced pain hypersensitivity.

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“…Moreover, these data are not unambiguously clear. Thus, it was reported that NF-B activity in different cell types is either increased (Liu and Wong, 2005;El-Hage et al, 2008) or decreased (Wang et al, 2008;Börner et al, 2009b) in response to opioids. Therefore, we investigated in detail molecular mechanisms underlying the regulation of NF-B by morphine in neuronal cells.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of the Inhibition of Nuclear Factor-κB by Morphine in Neuronal Cells

Börner¹,

Höllt²,

Kraus³

2012

Mol Pharmacol

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Opioids potently modulate neuronal functions, for example, by regulating the activity of transcription factors. Here, we investigated the effect of morphine on the activity of the transcription factor nuclear factor B (NF-B). Establishing cellular models for our investigations, we demonstrated that NF-B mediated the tumor necrosis factor (TNF)-induced transcription of the cannabinoid receptor type 1 gene in primary fetal striatal neurons from rats and the human neuroblastoma cell line SH SY5Y. The activity of NF-B in these models was strongly inhibited by morphine, which was achieved by a marked up-regulation of the inhibitor of nuclear factor-B (IB). The opioid-induced up-regulation of IB was dependent on the transcription factors NF-B itself and activator protein-1 (AP-1). In fact, stimulation of the cells with morphine resulted in a transient activation of NF-B and a strong induction of c-Fos, one of the constituents of AP-1. This resulted in IB levels significantly exceeding the basal, constitutive levels of IB. These data, together with experiments in which AP-1 and IB were down-regulated by decoy oligonucleotides and siRNA, suggest that the morphineinduced activation of AP-1 and the subsequent overexpression of IB are key factors in the inhibition of NF-B by the drug. In contrast, stimulation of primary neurons from rats and SH SY5Y cells with TNF, which is a classic activator of NF-B, resulted in a resynthesis of IB, in which the basal levels of IB were restored only but did not result in an activation of AP-1 and overexpression of IB.

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Morphine Exacerbates HIV-1 Tat-Induced Cytokine Production in Astrocytes through Convergent Effects on [Ca2+]i, NF-κB Trafficking and Transcription

Cited by 109 publications

References 60 publications

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Toll-like receptor 4-mediated nuclear factor-κB activation in spinal cord contributes to chronic morphine-induced analgesic tolerance and hyperalgesia in rats

Mechanisms of the Inhibition of Nuclear Factor-κB by Morphine in Neuronal Cells

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