TY - JOUR
T1 - Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice
AU - Cruz, Hans G.
AU - Berton, Frédérique
AU - Sollini, Monica
AU - Blanchet, Christophe
AU - Pravetoni, Marco
AU - Wickman, Kevin
AU - Lüscher, Christian
PY - 2008/4/9
Y1 - 2008/4/9
N2 - 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.
AB - 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.
KW - DSP4
KW - G-protein-gated inwardly rectifying K channel
KW - GIRK
KW - Locus ceruleus
KW - Noradrenaline
KW - Wild type
KW - μ opioid receptor
UR - http://www.scopus.com/inward/record.url?scp=43049170426&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=43049170426&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.0267-08.2008
DO - 10.1523/JNEUROSCI.0267-08.2008
M3 - Article
C2 - 18400906
AN - SCOPUS:43049170426
SN - 0270-6474
VL - 28
SP - 4069
EP - 4077
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 15
ER -