Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice.
J Neurosci
; 28(15): 4069-77, 2008 Apr 09.
Article
en En
| MEDLINE
| ID: mdl-18400906
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Síndrome de Abstinencia a Sustancias
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Fibras Adrenérgicas
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Canales de Potasio Rectificados Internamente Asociados a la Proteína G
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Analgésicos Opioides
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Morfina
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Inhibición Neural
Límite:
Animals
Idioma:
En
Revista:
J Neurosci
Año:
2008
Tipo del documento:
Article
País de afiliación:
Suiza