Scientific Article
unige:1047 
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Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice |
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| Authors | ||
| Published in | The Journal of neuroscience. 2008, vol. 28, no. 15, p. 4069-7407 | |
| Abstract | Although morphine induces both analgesia and dependence through mu-opioid receptors (MORs), the respective contributions of the intracellular effectors engaged by MORs remain unknown. To examine the contribution of G-protein-gated inwardly rectifying K(+) (GIRK, Kir3) channels to morphine dependence and analgesia, we quantified naloxone-precipitated withdrawal behavior and morphine analgesia using GIRK knock-out ((-/-)) mice. The morphine withdrawal syndrome was strongly attenuated, whereas morphine analgesia was mostly preserved in mice lacking both GIRK2 and GIRK3 (GIRK2/3(-/-) mice). In acute slices containing the locus ceruleus (LC) from GIRK2/3(-/-) mice, the increase in spontaneous firing typically associated with morphine withdrawal was absent. Moreover, although morphine elicited normal presynaptic inhibition in the LC, postsynaptic GIRK currents were completely abolished in GIRK2/3(-/-) mice. Altogether, these data suggested that morphine-evoked postsynaptic inhibition of the LC was required for the induction of dependence. Consistent with this hypothesis, morphine withdrawal behavior was rescued in GIRK2/3(-/-) mice by ablation of adrenergic fibers using the neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine. Our data suggest that inhibition of adrenergic tone is required for the induction of dependence, and that channels containing GIRK2 and GIRK3 serve as an inhibitory gate. | |
| Keywords | Adrenergic Fibers/drug effects — Analgesia — Analgesics, Opioid/adverse effects — Animals — Benzylamines/pharmacology — Electrophysiology — G Protein-Coupled Inwardly-Rectifying Potassium Channels/deficiency — Locus Coeruleus/metabolism/physiopathology — Mice — Mice, Knockout — Morphine/adverse effects — Naloxone/pharmacology — Narcotic Antagonists/pharmacology — Neural Inhibition — Neurotoxins/pharmacology — Substance Withdrawal Syndrome/metabolism/physiopathology — Substance-Related Disorders/metabolism/physiopathology | |
| Identifiers | PMID: 18400906 | |
| Full text |
 Article (Accepted version) (102 Kb) -  Limited access to UNIGE Supplemental data - I (115 Kb) - Limited access to UNIGE Supplemental data - II (53 Kb) - Limited access to UNIGE Supplemental data - III (358 Kb) - Limited access to UNIGEOther version: http://www.jneurosci.org/cgi/content/full/28/15/4069 |
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| Structures | ||
| Research group | Mécanismes cellulaires de la dépendance et de l'addiction (520) | |
| Citation (ISO format) | CRUZ, Joana et al. Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice. In: The Journal of neuroscience, 2008, vol. 28, n° 15, p. 4069-7407. doi: 10.1523/JNEUROSCI.0267-08.2008 https://archive-ouverte.unige.ch/unige:1047 |
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