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Scientific article
English

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

Contributors

Cruz, Joana; Berton, Frédérique; Sollini, Monica; Blanchet, Christophe; Pravetoni, Marco; Wickman, Kevin; Luescher, Christian

Published in

The Journal of neuroscience, vol. 28, no. 15, p. 4069-7407

Publication date

2008

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

UNIGE affiliation entities

UNIGE research groups

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 (Published version)

Secondary files (3)

Supplemental data - Supplemental text and legends
Supplemental data - Supplemental table 1
Supplemental data - Supplemental Figure 1

Identifiers

Additional URL for this publication

http://www.jneurosci.org/cgi/content/full/28/15/4069

Journal ISSN

0270-6474
700views
2downloads

Technical informations

Creation

27/02/2009 15:10:00

First validation

27/02/2009 15:10:00

Update

14/10/2025 07:13:49

Status update

03/09/2024 13:31:44

Last indexation

02/11/2026 16:36:14
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