Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice.
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.
Cruz
Hans G
HG
Department of Basic Neurosciences , University of Geneva, CH-1211 Geneva, Switzerland.
Berton
Frédérique
F
Sollini
Monica
M
Blanchet
Christophe
C
Pravetoni
Marco
M
Wickman
Kevin
K
Lüscher
Christian
C
D000320:Adrenergic Fibers / Q000187:drug effects; D000698:Analgesia; D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D004594:Electrophysiology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000172:deficiency*; D066298:In Vitro Techniques; D008125:Locus Coeruleus / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000009:adverse effects*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009433:Neural Inhibition; D009498:Neurotoxins / Q000494:pharmacology; D013375:Substance Withdrawal Syndrome / Q000378:metabolism / Q000503:physiopathology*; D019966:Substance-Related Disorders / Q000378:metabolism / Q000503:physiopathology
D000701:Analgesics, Opioid; D001596:Benzylamines; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; C497069:Kcnj6 protein, mouse; D009292:Narcotic Antagonists; D009498:Neurotoxins; D009270:Naloxone; D009020:Morphine; C012102:DSP 4