Cruz HG Berton F Sollini M Blanchet C Pravetoni M Wickman K Lüscher C 2008 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. application/pdf https://sonar.ch/global/documents/220151 eng info:eu-repo/semantics/altIdentifier/doi/10.1523/JNEUROSCI.0267-08.2008 info:eu-repo/semantics/altIdentifier/pmid/18400906 info:eu-repo/semantics/openAccess 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 Absence and rescue of morphine withdrawal in GIRK/Kir3 knock-out mice. http://purl.org/coar/resource_type/c_6501