Evidence map›Paper›PMID 25241065›Full record

ArticleNeuroscience2014

Activation of adult rat CNS endothelial cells by opioid-induced toll-like receptor 4 (TLR4) signaling induces proinflammatory, biochemical, morphological, and behavioral sequelae.

P M Grace, K M Ramos, K M Rodgers, X Wang, M R Hutchinson, M T Lewis, K N Morgan, J L Kroll, F R Taylor, K A Strand and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuroscience, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.

0numbers the graph read from it
0cells of the map it votes in
37citing papers in PubMed
3.4field-weighted citation impact, top 7% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

37 citing papers in PubMed, 65 citations in OpenAlex.

  1. Article
  2. Article
  3. Article
  4. Review
  5. Article
  6. Article
  7. Article
  8. Morphine-3-Glucuronide, Physiology and Behavior.Frontiers in molecular neuroscience · 2022
    Review
  9. Review
  10. Temporal Contribution of Myeloid-Lineage TLR4 to the Transition to Chronic Pain: A Focus on Sex Differences.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2021
    Article
  11. Article
  12. Article
  13. Article
  14. Opioid-Mediated HIV-1 Immunopathogenesis.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2020
    Review
  15. Review
  16. Article
  17. Review
  18. Toll-Like Receptor 4 Promotes Th17 Lymphocyte Infiltration Via CCL25/CCR9 in Pathogenesis of Experimental Autoimmune Encephalomyelitis.Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology · 2019
    Article
  19. Article
  20. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

21 authors at 4 institutions in 2 countries.

P M GraceDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA. Electronic address: peter.grace@colorado.edu.
K M RamosDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
K M RodgersDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
X WangDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA; Department of Chemistry and Biochemistry, and the BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, USA.
M R HutchinsonDiscipline of Physiology, School of Medical Sciences, University of Adelaide, South Australia, Australia.
M T LewisDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
K N MorganDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
J L KrollDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
F R TaylorDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
K A StrandDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
Y ZhangDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
D BerkelhammerDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
M G HueyDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
L I GreeneDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
T A CochranDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
H YinDepartment of Chemistry and Biochemistry, and the BioFrontiers Institute, University of Colorado Boulder, Boulder, CO, USA.
D S BarthDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
K W JohnsonMediciNova, Inc., San Diego, CA, USA.
K C RiceChemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, USA.
S F MaierDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
L R WatkinsDepartment of Psychology and the Center for Neuroscience, University of Colorado Boulder, Boulder, CO, USA.
University of Colorado Boulder · USMediciNova (United States) · USNational Institute on Alcohol Abuse and Alcoholism · USUniversity of Adelaide · AU

Funding

Preventing Transition of Acute-to-Chronic Neuropathic Pain: Models, Mechanisms &R01DE021966 · NIDCR · UNIVERSITY OF COLORADO · PI BARTH, DANIEL S., FLESHNER, MONIKA · 2011 to 2015
$2.0M
Exploring the Potential of Glia for Regulating Clinically Relevant Opiod ActionsR01DA023132 · NIDA · UNIVERSITY OF COLORADO · PI WATKINS, LINDA · 2008 to 2012
$1.9M
Optoid Analgesics: Modulation of Trigeminal & Spinal Glial ActivationR01DE017782 · NIDCR · UNIVERSITY OF COLORADO · PI WATKINS, LINDA · 2006 to 2010
$1.9M
Exogenous Chemical Probes of TLR-Mediated NeuroinflammationR01GM101279 · NIGMS · UNIVERSITY OF COLORADO · PI YIN, HANG HUBERT · 2013 to 2017
$1.4M
Dissecting Cell Signaling Mediated by Protein-Protein Interactions in MembranesR01GM103843 · NIGMS · UNIVERSITY OF COLORADO · PI YIN, HANG HUBERT · 2013 to 2016
$1.3M
Immune and Gilia Regulation of Pain & Analgesic ActionsK05DA024044 · NIDA · UNIVERSITY OF COLORADO · PI WATKINS, LINDA · 2008 to 2012
$616k
Role of spinal oligodendrocytes and endothelial cells in exaggerated pain statesF32NS066665 · NINDS · UNIVERSITY OF COLORADO · PI RAMOS, KHARA M · 2009 to 2012
$128k
Intramural NIH HHSNIDA NIH HHS DA023132NIDA NIH HHS DA024044NIDA NIH HHS K05 DA024044NIDA NIH HHS R01 DA023132NIDCR NIH HHS DE017782NIDCR NIH HHS R01 DE017782NIDCR NIH HHS R01 DE021966NIGMS NIH HHS GM101279NIGMS NIH HHS GM103843NIGMS NIH HHS R01 GM101279NINDS NIH HHS F32 NS066665NINDS NIH HHS F32NS066665
6 · The paper itself

Abstract

CNS immune signaling contributes to deleterious opioid effects including hyperalgesia, tolerance, reward, and dependence/withdrawal. Such effects are mediated by opioid signaling at toll-like receptor 4 (TLR4), presumptively of glial origin. Whether CNS endothelial cells express TLR4 is controversial. If so, they would be well positioned for activation by blood-borne opioids, contributing to opioid-induced pro-inflammatory responses. These studies examined adult primary rat CNS endothelial cell responses to (-)-morphine or its mu opioid receptor (MOR)-inactive metabolite morphine-3-glucuronide (M3G), both known TLR4 agonists. We demonstrate that adult rat CNS endothelial cells express functional TLR4. M3G activated nuclear factor kappaB (NF-κB), increased tumor necrosis factor-α (TNFα) and cyclooxygenase-2 (COX2) mRNAs, and released prostaglandin E2 (PGE2) from these cells. (-)-Morphine-induced upregulation of TNFα mRNA and PGE2 release were unmasked by pre-treatment with nalmefene, a MOR antagonist without TLR4 activity (unlike CTAP, shown to have both MOR- and TLR4-activity), suggestive of an interplay between MOR and TLR4 co-activation by (-)-morphine. In support, MOR-dependent Protein Kinase A (PKA) opposed TLR4 signaling, as PKA inhibition (H-89) also unmasked (-)-morphine-induced TNFα and COX2 mRNA upregulation. Intrathecal injection of CNS endothelial cells, stimulated in vitro with M3G, produced TLR4-dependent tactile allodynia. Further, cortical suffusion with M3G in vivo induced TLR4-dependent vasodilation. Finally, endothelial cell TLR4 activation by lipopolysaccharide and/or M3G was blocked by the glial inhibitors AV1013 and propentofylline, demonstrating endothelial cells as a new target of such drugs. These data indicate that (-)-morphine and M3G can activate CNS endothelial cells via TLR4, inducing proinflammatory, biochemical, morphological, and behavioral sequelae. CNS endothelial cells may have previously unanticipated roles in opioid-induced effects, in phenomena blocked by presumptive glial inhibitors, as well as TLR4-mediated phenomena more broadly.

Indexed as

AnimalsCentral Nervous SystemCyclic AMP-Dependent Protein KinasesCyclooxygenase 2DinoprostoneEndothelial CellsHyperalgesiaMaleMorphineMorphine DerivativesNarcoticsNeurogliaNeuroimmunomodulationNF-kappa BRats, Sprague-DawleyReceptors, Opioid, muCyclic AMP-Dependent Protein KinasesCyclooxygenase 2DinoprostoneMorphinemorphine-3-glucuronideMorphine DerivativesNarcoticsNF-kappa BPtgs2 protein, ratReceptors, Opioid, muRNA, MessengerTlr4 protein, ratToll-Like Receptor 4Tumor Necrosis Factor-alphaCTAPendothelial cellM3GmorphinenalmefeneTLR4

Identifiers

PMID25241065
PMCPMC4250379
OpenAlexW2033189137

What OpenQuestion holds

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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.