Evidence map›Paper›PMID 31253357›Full record

ArticleBritish journal of anaesthesia2019

The mitochondrial calcium uniporter contributes to morphine tolerance through pCREB and CPEB1 in rat spinal cord dorsal horn.

K Takahashi, H Yi, J Gu, D Ikegami, S Liu, T Iida, Y Kashiwagi, C Dong, T Kunisawa, S Hao

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

Article in British journal of anaesthesia, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.

0numbers the graph read from it
0cells of the map it votes in
10citing papers in PubMed
1.2field-weighted citation impact, top 21% 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

10 citing papers in PubMed, 18 citations in OpenAlex.

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  4. Mitochondrial CaJournal of cellular physiology · 2025
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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

10 authors at 2 institutions in 2 countries.

K TakahashiDepartment of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Japan.
H YiDepartment of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
J GuDepartment of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
D IkegamiDepartment of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
S LiuDepartment of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
T IidaDepartment of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Japan.
Y KashiwagiDepartment of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA.
C DongBiostatistics Division, Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
T KunisawaDepartment of Anesthesiology and Critical Care Medicine, Asahikawa Medical University, Asahikawa, Japan.
S HaoDepartment of Anesthesiology, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address: shao@med.miami.edu.
University of Miami · USAsahikawa Medical University · JP

Funding

Role of Gut Microbiome in HIV/Opioid Induced Peripheral NeuropathyR01DA047089 · NIDA · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI HAO, SHUANGLIN, RAMAKRISHNAN, SUNDARAM · 2018 to 2022
$2.3M
A new pathway of spinal neurons in neuropathic pain induced by HIV with opioidR01DA047157 · NIDA · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI HAO, SHUANGLIN · 2018 to 2022
$2.1M
Neuropathic mechanisms and gene therapy on opioid dependenceR01DA034749 · NIDA · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · PI HAO, SHUANGLIN · 2014 to 2018
$1.7M
HIV and NRTI's-induced painful pathogenic mechanisms and gene therapyR01NS066792 · NINDS · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI HAO, SHUANGLIN · 2010 to 2014
$1.6M
NIDA NIH HHS R01 DA034749NIDA NIH HHS R01 DA047089NIDA NIH HHS R01 DA047157NINDS NIH HHS R01 NS066792
6 · The paper itself

Abstract

backgroundThe long-term use of opioid analgesics is limited by the development of unwanted side-effects, such as tolerance. The molecular mechanisms of morphine anti-nociceptive tolerance are still unclear. The mitochondrial calcium uniporter (MCU) is involved in painful hyperalgesia, but the role of MCU in morphine tolerance has not been uncharacterised.

methodsRats received intrathecal injection of morphine for 7 days to induce morphine tolerance. The mechanical withdrawal threshold was measured using von Frey filaments, and thermal latency using the hotplate test. The effects of an MCU inhibitor, antisense oligodeoxynucleotide against cyclic adenosine monophosphate response element (CRE)-binding protein (CREB) or cytoplasmic polyadenylation element-binding protein 1 (CPEB1) in morphine tolerance were examined.

resultsSpinal morphine tolerance was associated with an increased expression of neuronal MCU, phospho-CREB (pCREB), and CPEB1 in the spinal cord dorsal horn. MCU inhibition increased the mechanical threshold and thermal latency, and reduced the accumulation of mitochondrial calcium in morphine tolerance. Intrathecal antisense oligodeoxynucleotide against CREB or CPEB1 restored the anti-nociceptive effects of morphine compared with mismatch oligodeoxynucleotide in von Frey test and hotplate test. Chromatin immunoprecipitation with quantitative PCR assay showed that CREB knockdown reduced the interaction of pCREB with the ccdc109a gene (encoding MCU expression) promoter and decreased the MCU mRNA transcription. RNA immunoprecipitation assay suggested that CPEB1 binds to the MCU mRNA 3' untranslated region. CPEB1 knockdown decreased the expression of MCU protein.

conclusionsThese findings suggest that spinal MCU is regulated by pCREB and CPEB1 in morphine tolerance, and that inhibition of MCU, pCREB, or CPEB1 may be useful in preventing the development of opioid tolerance.

Indexed as

Analgesics, OpioidAnimalsCalcium ChannelsCREB-Binding ProteinDrug ToleranceMaleModels, AnimalMorphinePolymerase Chain ReactionRatsRats, Sprague-DawleyRNA-Binding ProteinsSpinal Cord Dorsal HornAnalgesics, OpioidCalcium ChannelsCPEB1 protein, ratCREB-Binding ProteinCrebbp protein, ratmitochondrial calcium uniporterMorphineRNA-Binding ProteinscalciumCPEBCREBmitochondrial calcium uniportermorphineopioidsopioid tolerance

Identifiers

PMID31253357
PMCPMC6676161
OpenAlexW2953783713

What OpenQuestion holds

Textmetadata
Read underepoch 390

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.