Scientific article

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

Published inThe Journal of neuroscience, vol. 28, no. 15, p. 4069-7407
Publication date2008

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.

  • 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
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
Main files (1)
Article (Accepted version)
Secondary files (3)
ISSN of the journal0270-6474

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