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Escaping the adverse effects of morphine

Despite its beneficial effects against pain, morphine use is accompanied by adverse effects such as constipation, nausea, vomiting, respiratory depression, and potential dependence on the drug.  A research team led by Alain Eschalier, Director of Inserm Unit 1107, Neuro-Dol, in Clermont Ferrand, has just shown that it is possible to separate these two types of effects, and retain the desired analgesic effect without the adverse effects. These results are published in the 17 December 2013 issue of Nature Communications.


3D visualization of morphine’s receptor when it is associated with its antagonist  © Kobilka Lab

The beneficial and adverse effects of morphine and other opiate drugs depend on the same receptor, the mu receptor. To separate them, the researchers worked on proteins located downstream of the receptor. They chose TREK-1, a channel that inhibits neuronal activity and is known from previous work to be involved in pain.

In the present study, the research team showed, using mice, that this channel is involved in the analgesic effect of morphine without any role in its adverse effects. Indeed, when the gene is deleted in mice, the analgesic effect of morphine tested in clinical pain models (post-operational type pain, for example) is reduced.

“The TREK-1 channels are essential for the analgesic effect of morphine, but are not involved in its adverse effects, since neither constipation, respiratory depression, nor physical dependence is changed in animals in which they have been deleted.

Direct activation of these channels may thus lead to a morphine-type analgesia without inducing the side-effects associated with this type of drug,” concludes Alain Eschalier, last author of the study.

The team is currently working on the synthesis of new TREK-1-activating drugs with members of the Analgesia Institute (a public-private partnership).

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Researcher Contact

Directeur Unité Inserm 1107 “Neuro-dol” (Inserm/Université d’Auvergne) à Clermont Ferrand
Responsable de l’équipe “Pharmacologie fondamentale et clinique de la douleur”
+33 4 73 17 82 30



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

Maïly Devilliers1,2,*, Jérôme Busserolles1,2,*, Stéphane Lolignier1,2, Emmanuel Deval3,4,5, Vanessa Pereira1,2, Abdelkrim Alloui1,2, Marine Christin3,4,5, Bruno Mazet6, Patrick Delmas6, Jacques Noel3,4,5, Michel Lazdunski3,4 & Alain Eschalier1,2,7

1 Clermont Université´, Université´ d’Auvergne, Pharmacologie fondamentale et clinique de la douleur, 63000 Clermont-Ferrand, France.
2 Inserm, U 1107, Neuro-Dol, 63000 Clermont-Ferrand, France.
3 Université´ de Nice Sophia Antipolis, 06560 Valbonne, France.
4 CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 660 Route des Lucioles Sophia Antipolis, 06560 Valbonne, France.
5 LabEx Ion Channel Science and Therapeutics, 06560 Valbonne, France.
6 Aix Marseille Université´, CNRS, CRN2M UMR 7286, 13344 cedex 15, Marseille, France.
7 CHU Clermont-Ferrand, Service de pharmacologie, F-63003 Clermont-Ferrand, France.