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The Journal of Neuroscience, April 9, 2008, 28(15):4069-4077; doi:10.1523/JNEUROSCI.0267-08.2008

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Behavioral/Systems/Cognitive
Absence and Rescue of Morphine Withdrawal in GIRK/Kir3 Knock-out Mice

Hans G. Cruz,¹ Frédérique Berton,¹ Monica Sollini,¹ Christophe Blanchet,¹ Marco Pravetoni,³ Kevin Wickman,³ and Christian Lüscher^1,2

¹Department of Basic Neurosciences and ²Clinic of Neurology, University of Geneva, CH-1211 Geneva, Switzerland, and ³Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota 55455

Correspondence should be addressed to either Christian Lüscher or Kevin Wickman at the above address. Email: Christian.Luscher{at}medecine.unige.ch or Email: wickm002{at}umn.edu.

Although morphine induces both analgesia and dependence through µ-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.

Key words: GIRK; G-protein-gated inwardly rectifying K⁺ channel; locus ceruleus; µ opioid receptor; noradrenaline; wild type; DSP4

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Received Sept. 12, 2007; revised Feb. 26, 2008; accepted March 2, 2008.

Correspondence should be addressed to either Christian Lüscher or Kevin Wickman at the above address. Email: Christian.Luscher{at}medecine.unige.ch or Email: wickm002{at}umn.edu.

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