Evidence map›Paper›PMID 27247388›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2016

Morphine paradoxically prolongs neuropathic pain in rats by amplifying spinal NLRP3 inflammasome activation.

Peter M Grace, Keith A Strand, Erika L Galer, Daniel J Urban, Xiaohui Wang, Michael V Baratta, Timothy J Fabisiak, Nathan D Anderson, Kejun Cheng, Lisa I Greene and 9 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 206 papers.

0numbers the graph read from it
0cells of the map it votes in
206citing papers in PubMed
23.0field-weighted citation impact, top 1% 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

206 citing papers in PubMed, 374 citations in OpenAlex.

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  16. Loss of lysosomal acid lipase contributes to Alzheimer's disease pathology and cognitive decline.Alzheimer's & dementia : the journal of the Alzheimer's Association · 2025
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146 more citing papers are in PubMed but not listed here.

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

19 authors at 3 institutions in 3 countries.

Peter M GraceDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309; Discipline of Pharmacology, School of Medicine, University of Adelaide, Adelaide, SA 5005, Australia; peter.grace@colorado.edu.ORCID 0000-0002-8999-1220
Keith A StrandDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Erika L GalerDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Daniel J UrbanDepartment of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;
Xiaohui WangDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309; Chemical Biology Laboratory, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, Jilin 130022, China; Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309; BioFrontiers Institute, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Michael V BarattaDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Timothy J FabisiakDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Nathan D AndersonDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Kejun ChengChemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
Lisa I GreeneDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Debra BerkelhammerDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Yingning ZhangDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Amanda L EllisDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Hang Hubert YinDepartment of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80309; BioFrontiers Institute, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309; Center of Basic Molecular Science, Department of Chemistry, Tsinghua University, Beijing 100082, China.
Serge CampeauDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Kenner C RiceChemical Biology Research Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20892;
Bryan L RothDepartment of Pharmacology, University of North Carolina, Chapel Hill, NC 27599;
Steven F MaierDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
Linda R WatkinsDepartment of Psychology and Neuroscience, University of Colorado, Boulder, CO 80309; The Center for Neuroscience, University of Colorado, Boulder, CO 80309;
University of Colorado Boulder · USNational Institute on Drug Abuse · USUniversity of North Carolina at Chapel Hill · US

Funding

Medicinal Chemistry of Drugs Acting on Central and Peripheral Opioid ReceptorsZIADA000527 · NIDA · NATIONAL INSTITUTE ON DRUG ABUSE · PI RICE, KENNER · 2009 to 2025
$23.2M
Medicinal Chemistry of Drugs Acting on Toll-like ReceptorsZIADA000530 · NIDA · NATIONAL INSTITUTE ON DRUG ABUSE · PI RICE, KENNER · 2009 to 2020
$4.0M
Diterpines as Selective Kappa Opioid Receptor AgonistsR01DA017204 · NIDA · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ROTH, BRYAN L. · 2003 to 2014
$3.2M
DREADD2.0: AN ENHANCED CHEMOGENETIC TOOLKITU01MH105892 · NIMH · UNIV OF NORTH CAROLINA CHAPEL HILL · PI JIN, JIAN, KASH, THOMAS L. · 2014 to 2016
$3.0M
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
Exogenous Chemical Probes of TLR-Mediated NeuroinflammationR01GM101279 · NIGMS · UNIVERSITY OF COLORADO · PI YIN, HANG HUBERT · 2013 to 2017
$1.4M
NIDA NIH HHS R01 DA017204NIDA NIH HHS R01 DA023132NIDCR NIH HHS R01 DE021966NIGMS NIH HHS R01 GM101279NIMH NIH HHS U01 MH105892
6 · The paper itself

Abstract

Opioid use for pain management has dramatically increased, with little assessment of potential pathophysiological consequences for the primary pain condition. Here, a short course of morphine, starting 10 d after injury in male rats, paradoxically and remarkably doubled the duration of chronic constriction injury (CCI)-allodynia, months after morphine ceased. No such effect of opioids on neuropathic pain has previously been reported. Using pharmacologic and genetic approaches, we discovered that the initiation and maintenance of this multimonth prolongation of neuropathic pain was mediated by a previously unidentified mechanism for spinal cord and pain-namely, morphine-induced spinal NOD-like receptor protein 3 (NLRP3) inflammasomes and associated release of interleukin-1β (IL-1β). As spinal dorsal horn microglia expressed this signaling platform, these cells were selectively inhibited in vivo after transfection with a novel Designer Receptor Exclusively Activated by Designer Drugs (DREADD). Multiday treatment with the DREADD-specific ligand clozapine-N-oxide prevented and enduringly reversed morphine-induced persistent sensitization for weeks to months after cessation of clozapine-N-oxide. These data demonstrate both the critical importance of microglia and that maintenance of chronic pain created by early exposure to opioids can be disrupted, resetting pain to normal. These data also provide strong support for the recent "two-hit hypothesis" of microglial priming, leading to exaggerated reactivity after the second challenge, documented here in the context of nerve injury followed by morphine. This study predicts that prolonged pain is an unrealized and clinically concerning consequence of the abundant use of opioids in chronic pain.

Indexed as

AnimalsChronic PainClozapineInflammasomesInterleukin-1betaMaleMicrogliaMorphineNeuralgiaNLR Family, Pyrin Domain-Containing 3 ProteinRatsRats, Inbred F344Rats, Sprague-DawleySpinal Cord Dorsal HornClozapineclozapine N-oxideIL1B protein, ratInflammasomesInterleukin-1betaMorphineNLR Family, Pyrin Domain-Containing 3 ProteinNlrp3 protein, ratDAMPdanger signalsopioid-induced hyperalgesiaP2X7RTLR4

Identifiers

PMID27247388
PMCPMC4914184
OpenAlexW2409306902

What OpenQuestion holds

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Registered trials

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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.