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Activation of TREK-1 by morphine results in analgesia without adverse side effects

Nature Communications volume 4, Article number: 2941 (2013) | Download Citation

Abstract

Morphine is the gold-standard pain reliever for severe acute or chronic pain but it also produces adverse side effects that can alter the quality of life of patients and, in some rare cases, jeopardize the vital prognosis. Morphine elicits both therapeutic and adverse effects primarily through the same μ opioid receptor subtype, which makes it difficult to separate the two types of effects. Here we show that beneficial and deleterious effects of morphine are mediated through different signalling pathways downstream from μ opioid receptor. We demonstrate that the TREK-1 K+ channel is a crucial contributor of morphine-induced analgesia in mice, while it is not involved in morphine-induced constipation, respiratory depression and dependence—three main adverse effects of opioid analgesic therapy. These observations suggest that direct activation of the TREK-1 K+ channel, acting downstream from the μ opioid receptor, might have strong analgesic effects without opioid-like adverse effects.

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Acknowledgements

We wish to thank Valérie Julia for providing the plethysmometric apparatus and Florian Lesage for providing knockout mice. This work was supported by grants from Agence Nationale de la Recherche (ANR-11-BSV4-022-01; ANR-09-MNPS-037-01), Fondation pour la Recherche sur le Cerveau (DEQ 20130326482), the Société Française d’Etude et de Traitement de la Douleur, région Auvergne and FEDER, Fondation Hamel.

Author information

Author notes

    • Maïly Devilliers
    •  & Jérôme Busserolles

    These authors contributed equally to this work

Affiliations

  1. Clermont Université, Université d’Auvergne, Pharmacologie fondamentale et clinique de la douleur, 63000 Clermont-Ferrand, France

    • Maïly Devilliers
    • , Jérôme Busserolles
    • , Stéphane Lolignier
    • , Vanessa Pereira
    • , Abdelkrim Alloui
    •  & Alain Eschalier
  2. Inserm, U 1107, Neuro-Dol, 63000 Clermont-Ferrand, France

    • Maïly Devilliers
    • , Jérôme Busserolles
    • , Stéphane Lolignier
    • , Vanessa Pereira
    • , Abdelkrim Alloui
    •  & Alain Eschalier
  3. Université de Nice Sophia Antipolis, 06560 Valbonne, France

    • Emmanuel Deval
    • , Marine Christin
    • , Jacques Noel
    •  & Michel Lazdunski
  4. CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 660 Route des Lucioles Sophia Antipolis, 06560 Valbonne, France

    • Emmanuel Deval
    • , Marine Christin
    • , Jacques Noel
    •  & Michel Lazdunski
  5. LabEx Ion Channel Science and Therapeutics, 06560 Valbonne, France

    • Emmanuel Deval
    • , Marine Christin
    •  & Jacques Noel
  6. Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344 cedex 15, Marseille, France

    • Bruno Mazet
    •  & Patrick Delmas
  7. CHU Clermont-Ferrand, Service de pharmacologie, F-63003 Clermont-Ferrand, France

    • Alain Eschalier

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Contributions

J.B. and M.D. conducted the experiments, analysed the data and participated in the preparation of the manuscript. A.A. participated to initiate the work and to behavioural experiments. J.N. conducted electrophysiological experiments and participated in the preparation of the manuscript. P.D. and B.M. were involved in experiments on colonic muscular wall activity. S.L. and V.P. were associated with behavioural experiments. M.C. and E.D. conducted electrophysiological experiments. A.E. and M.L. supervised the project, participated in data analysis and manuscript preparation.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Michel Lazdunski or Alain Eschalier.

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DOI

https://doi.org/10.1038/ncomms3941

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