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Title

Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice

Authors
Berton, Frédérique
Pravetoni, Marco
Wickman, Kevin
Published in 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 effectsAnalgesiaAnalgesics, Opioid/adverse effectsAnimalsBenzylamines/pharmacologyElectrophysiologyG Protein-Coupled Inwardly-Rectifying Potassium Channels/deficiencyLocus Coeruleus/metabolism/physiopathologyMiceMice, KnockoutMorphine/adverse effectsNaloxone/pharmacologyNarcotic Antagonists/pharmacologyNeural InhibitionNeurotoxins/pharmacologySubstance Withdrawal Syndrome/metabolism/physiopathologySubstance-Related Disorders/metabolism/physiopathology
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Other version: http://www.jneurosci.org/cgi/content/full/28/15/4069
Identifiers
PMID: 18400906
Structures
Research group Mécanismes cellulaires de la dépendance et de l'addiction (520)
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