1. Neuroscience
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Protective role of neuronal and lymphoid cannabinoid CB2 receptors in neuropathic pain

  1. David Cabañero
  2. Angela Ramírez-López
  3. Eva Drews
  4. Anne Schmöle
  5. David M Otte
  6. Agnieszka Wawrzczak-Bargiela
  7. Hector Huerga Encabo
  8. Sami Kummer
  9. Antonio Ferrer-Montiel
  10. Ryszard Przewlocki
  11. Andreas Zimmer
  12. Rafael Maldonado  Is a corresponding author
  1. Universitat Pompeu Fabra, Spain
  2. University of Bonn, Germany
  3. Polish Academy of Sciences, Poland
  4. Universidad Miguel Hernández, Spain
Research Article
  • Cited 10
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Cite this article as: eLife 2020;9:e55582 doi: 10.7554/eLife.55582

Abstract

Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects. Peripheral immune cells, neurons and glia express CB2, however the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2 knockouts and was increased in mice defective in neuronal CB2 knockouts suggestive of increased spontaneous pain. Interestingly, CB2-positive lymphocytes infiltrated the injured nerve and possible CB2transfer from immune cells to neurons was found. Lymphocyte CB2depletion also exacerbated JWH133 self-administration and inhibited antinociception. This work identifies a simultaneous activity of neuronal and lymphoid CB2that protects against spontaneous and evoked neuropathic pain.

Data availability

All experimental data and statistical analyses of this study are included in the manuscript and its supplementary files. Raw data and results of statistical analyses are provided in the Source Data File and its containing data sheets.

Article and author information

Author details

  1. David Cabañero

    Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1133-0908
  2. Angela Ramírez-López

    Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  3. Eva Drews

    Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Anne Schmöle

    Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. David M Otte

    Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Agnieszka Wawrzczak-Bargiela

    Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
    Competing interests
    The authors declare that no competing interests exist.
  7. Hector Huerga Encabo

    Immunology Unit, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  8. Sami Kummer

    Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
    Competing interests
    The authors declare that no competing interests exist.
  9. Antonio Ferrer-Montiel

    Institute of Research, Development and Innovation in Healthcare Biotechnology of Elche (IDiBE), Universidad Miguel Hernández, Elche, Alicante, Spain
    Competing interests
    The authors declare that no competing interests exist.
  10. Ryszard Przewlocki

    Department of Molecular Neuropharmacology, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
    Competing interests
    The authors declare that no competing interests exist.
  11. Andreas Zimmer

    Institute of Molecular Psychiatry, University of Bonn, Bonn, Germany
    Competing interests
    The authors declare that no competing interests exist.
  12. Rafael Maldonado

    Laboratory of Neuropharmacology, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Barcelona, Spain
    For correspondence
    rafael.maldonado@upf.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4359-8773

Funding

European Commission (FP7-602891-2)

  • Rafael Maldonado

Instituto de Salud Carlos III (RD12/0028/0023/FEDER)

  • Rafael Maldonado

Ministerio de Economía y Competitividad (SAF2014-59648-P)

  • Rafael Maldonado

Generalitat de Catalunya (2014-SGR-1547)

  • Rafael Maldonado

Generalitat de Catalunya (2018 FI_B 00207)

  • Angela Ramírez-López

Polish Ministry of Science and Education (3070/7.PR/2014/2)

  • Ryszard Przewlocki

Universidad Miguel Hernandez (UMH-PAR2019)

  • Antonio Ferrer-Montiel

Spanish Ministry of Science, Innovation and Universities (RTI2018-097189-B-C21)

  • Antonio Ferrer-Montiel

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: Animal handling and experiments were in accordance with protocols approved by the respective Animal Care and Use Committees of the PRBB, Departament de Territori i Habitatge of Generalitat de Catalunya and the Institute of Molecular Psychiatry and were performed in accordance with the European Communities Council Directive (2010/63/EU).

Reviewing Editor

  1. Allan Basbaum, University of California San Francisco, United States

Publication history

  1. Received: January 29, 2020
  2. Accepted: July 19, 2020
  3. Accepted Manuscript published: July 20, 2020 (version 1)
  4. Version of Record published: July 27, 2020 (version 2)
  5. Version of Record updated: August 3, 2020 (version 3)

Copyright

© 2020, Cabañero et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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