title: Activation of TREK-1 by morphine results in analgesia without adverse side effects.
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.
authors.affiliation: 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].
authors.forename: Maïly
authors.initials: M
authors.lastname: Devilliers
authors.affiliation: 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].
authors.forename: Jérôme
authors.initials: J
authors.lastname: Busserolles
authors.affiliation: 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.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Lolignier
authors.affiliation: 1] Université de Nice Sophia Antipolis, 06560 Valbonne, France [2] CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 660 Route des Lucioles Sophia Antipolis, 06560 Valbonne, France [3] LabEx Ion Channel Science and Therapeutics, 06560 Valbonne, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Deval
authors.affiliation: 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.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Pereira
authors.affiliation: 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.
authors.forename: Abdelkrim
authors.initials: A
authors.lastname: Alloui
authors.affiliation: 1] Université de Nice Sophia Antipolis, 06560 Valbonne, France [2] CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 660 Route des Lucioles Sophia Antipolis, 06560 Valbonne, France [3] LabEx Ion Channel Science and Therapeutics, 06560 Valbonne, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Christin
authors.affiliation: Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344 cedex 15, Marseille, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Mazet
authors.affiliation: Aix Marseille Université, CNRS, CRN2M UMR 7286, 13344 cedex 15, Marseille, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Delmas
authors.affiliation: 1] Université de Nice Sophia Antipolis, 06560 Valbonne, France [2] CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 660 Route des Lucioles Sophia Antipolis, 06560 Valbonne, France [3] LabEx Ion Channel Science and Therapeutics, 06560 Valbonne, France.
authors.forename: Jacques
authors.initials: J
authors.lastname: Noel
authors.affiliation: 1] Université de Nice Sophia Antipolis, 06560 Valbonne, France [2] CNRS, Institut de Pharmacologie Moléculaire et Cellulaire, UMR 7275, 660 Route des Lucioles Sophia Antipolis, 06560 Valbonne, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lazdunski
authors.affiliation: 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] CHU Clermont-Ferrand, Service de pharmacologie, F-63003 Clermont-Ferrand, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Eschalier
mesh_terms: D000698:Analgesia / Q000379:methods*; D000701:Analgesics, Opioid / Q000009:adverse effects / Q000627:therapeutic use; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003248:Constipation; D003433:Crosses, Genetic; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009020:Morphine / Q000009:adverse effects* / Q000627:therapeutic use*; D009270:Naloxone / Q000737:chemistry; D010146:Pain / Q000188:drug therapy; D059408:Pain Management; D024683:Potassium Channels, Tandem Pore Domain / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism; D012131:Respiratory Insufficiency; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D024683:Potassium Channels, Tandem Pore Domain; D017450:Receptors, Opioid, mu; C103742:potassium channel protein TREK-1; D009270:Naloxone; D009020:Morphine