Increased Brain Size and Cellular Content in Infant Rats Treated with an Opiate Antagonist

Zagon, Ian S.; McLaughlin, Patricia J.

doi:10.1126/science.6612331

Cited by 206 publications

(65 citation statements)

References 13 publications

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“…51,96 This may partially explain findings that exposure to the long-acting, MOPr, DOPr, and KOPr opioid antagonist, naltrexone, by itself increased the number of filopodia in morphine-exposed Tat(ϩ) DOX mice (Figure 4). 32,44,51 The increased filopodial density (an indication of neuroplasticity) may reflect novel Tat-opioid interactions occurring with altered endogenous opioid tone.…”

Section: Chronic Hiv-1 Tat Disrupts the Endogenous Opioid Systemmentioning

confidence: 96%

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Fitting

Bull

et al. 2010

The American Journal of Pathology

132

106

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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: Chronic Hiv-1 Tat Disrupts the Endogenous Opioid Systemmentioning

confidence: 96%

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Fitting

Bull

et al. 2010

The American Journal of Pathology

132

106

View full text Add to dashboard Cite

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“…There is considerable evidence that endogenous opioid peptides and their receptors are involved in the regulation of neural growth in vivo 10,11,12,33,50,54 . However, the realization that endogenous opioids directly modify neural growth is provided by recent in vitro studies where the endogenous opioid, [Met 5 ]enkephalin, has been shown to directly suppress the growth of astrocytes in primary cultures derived from the cerebral hemispheres of newborn mice 43,44 .…”

Section: Introductionmentioning

confidence: 99%

Morphine alters astrocyte growth in primary cultures of mouse glial cells: evidence for a direct effect of opiates on neural maturation

Stiene‐Martin

Gurwell

Hauser

1991

Developmental Brain Research

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SUMMARYTo determine whether exogenous opiate drugs with abuse liability directly modify neural growth, the present study investigated the effects of morphine on astrocyte proliferation and differentiation in primary cultures of murine glial cells. The results indicate that morphine decreases glial cell production in a dose-dependent, naloxone reversible manner. Most notably, gliogenesis virtually ceased in the presence of 10 −6 M morphine during the first week in culture, whereas 10 −8 M or 10 −10 M morphine caused an intermediate suppression of growth compared to control or 10 −6 M morphine treated cultures. Moreover, morphine-treatment inhibited [ 3 H]thymidine incorporation by glial fibrillary acidic protein (GFAP) immunoreactive, flat (type 1) astrocytes, suggesting that the decrease in glial cell production was due in part to an inhibition of astrocyte proliferation. Morphine also caused significant increases in both cytoplasmic area and process elaboration in flat (type 1) astrocytes indicating greater morphologic differentiation. In the above experiments, morphine-dependent alterations in astrocyte growth were antagonized by naloxone, indicating that morphine action was mediated by specific opioid receptors. These observations suggest that opiate drugs can directly modify neural growth by influencing two critical developmental events in astrocytes, i.e., inhibiting proliferation and inducing morphologic differentiation.

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“…Endogenous opioid systems are present during development and serve to modify nervous system maturation in the brain through the opioid receptor systems (52)(53)(54)(55). Since Ets-1 may contribute to the development of the mouse brain DOR system, it is implicated in the regulation the mouse brain development, which provides insight into the functions of Ets-1 in the developing mouse brain.…”

Section: Ets-1 Trans-activates Mouse ␦-Opioid Receptor Gene Promotermentioning

confidence: 99%

Transcriptional Regulation of Mouse δ-Opioid Receptor Gene

Sun

Loh

2001

Journal of Biological Chemistry

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Previously, we identified a minimum core promoter of the mouse ␦-opioid receptor (DOR) gene. The DOR promoter contains an E-box that binds upstream stimulatory factor and is crucial for the DOR promoter activity in NS20Y cells, a mouse neuronal cell line that constitutively expresses DOR. In the present study, we further analyzed the DOR promoter in NS20Y cells and have demonstrated that transcription factor Ets-1 binds to an Ets-1-binding site overlapping the E-box and trans-activates the DOR promoter by synergizing with upstream stimulatory factor in specific DNA binding. In addition, the Ets-1 DNA-binding domain is sufficient to play the functional role of Ets-1 in trans-activating the DOR promoter. Furthermore, through in vivo cross-linking assays and Northern blot analyses, we have demonstrated that Ets-1 binds to the DOR promoter in the neonatal mouse brain and that overexpressed Ets-1 can significantly enhance the expression of DOR mRNA in primary neonatal mouse neuronal cells. Collectively, our data suggest that Ets-1 functions as a trans-activator of the DOR promoter in the neonatal mouse brain and thus may contribute to the development of the mouse brain DOR system.Opioids are the preferred clinical analgesics for severe pain. Three major types of opioid receptors (ORs), 1 , ␦, and , have been cloned and shown to belong to the G protein-coupled receptor superfamily (1). Although all three ORs mediate opioid-induced analgesia, each receptor type exhibits a distinct pharmacological profile as well as a unique pattern of temporal and spatial expression (2-3).The localization of the ␦-opioid receptor (DOR) generally matches the pharmacological action sites of ␦-opioids (2). In addition, it has been reported that the expression levels of DOR can determine the DOR agonist's activities (4). Thus, understanding the molecular mechanism underlying the spatiotemporal expression of DOR may raise the possibility of maximizing the pharmacological benefits of ␦-opioids by manipulation of the DOR expression levels.DOR is mainly confined to the central nervous system. There is a strong correlation between the spatiotemporal presence of DOR mRNA and ␦-opioid-binding sites (5). In addition, levels of DOR mRNA as well as ␦-opioid-binding sites can be regulated by various agents in some neuronal cell lines. For example, nerve growth factor (6), ethanol (7), or retinoic acid (8) can up-regulate DOR mRNA and ␦-opioid-binding sites. On the other hand, activation of the protein kinase A pathway by forskolin or cyclic AMP analogues results in down-regulation of DOR mRNA and ␦-opioid-binding sites (9). All of these studies suggest that the expression of DOR is subjected to several regulation mechanisms at the transcriptional level. Therefore, study of the transcriptional regulation of DOR gene will provide insights into the spatiotemporal expression of DOR.Previously, we identified a minimum core promoter of the mouse DOR gene. We found that an E box and a GC box in the DOR promoter are crucial for the DOR promoter activity in N...

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Increased Brain Size and Cellular Content in Infant Rats Treated with an Opiate Antagonist

Cited by 206 publications

References 13 publications

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Interactive Comorbidity between Opioid Drug Abuse and HIV-1 Tat

Morphine alters astrocyte growth in primary cultures of mouse glial cells: evidence for a direct effect of opiates on neural maturation

Transcriptional Regulation of Mouse δ-Opioid Receptor Gene

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