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

Hans G. Cruz, Frédérique Berton, Monica Sollini, Christophe Blanchet, Marco Pravetoni, Kevin Wickman, Christian Lüscher

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53 Scopus citations

Abstract

Although morphine induces both analgesia and dependence through μ-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.

Original languageEnglish (US)
Pages (from-to)4069-4077
Number of pages9
JournalJournal of Neuroscience
Volume28
Issue number15
DOIs
StatePublished - Apr 9 2008

Keywords

  • DSP4
  • G-protein-gated inwardly rectifying K channel
  • GIRK
  • Locus ceruleus
  • Noradrenaline
  • Wild type
  • μ opioid receptor

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