Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice.
- Cruz HG Department of Basic Neurosciences , University of Geneva, CH-1211 Geneva, Switzerland.
- Berton F
- Sollini M
- Blanchet C
- Pravetoni M
- Wickman K
- Lüscher C
- 2008-04-11
Published in:
- The Journal of neuroscience : the official journal of the Society for Neuroscience. - 2008
Adrenergic Fibers
Analgesia
Analgesics, Opioid
Animals
Benzylamines
Electrophysiology
G Protein-Coupled Inwardly-Rectifying Potassium Channels
In Vitro Techniques
Locus Coeruleus
Mice
Mice, Knockout
Morphine
Naloxone
Narcotic Antagonists
Neural Inhibition
Neurotoxins
Substance Withdrawal Syndrome
Substance-Related Disorders
English
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.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1523/JNEUROSCI.0267-08.2008
- PMID 18400906
- Persistent URL
- https://sonar.ch/global/documents/220151
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