title: A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia.
abstract: The signaling molecule RGS9-2 is a potent modulator of G-protein-coupled receptor function in striatum. Our earlier work revealed a critical role for RGS9-2 in the actions of the μ-opioid receptor (MOR) agonist morphine. In this study, we demonstrate that RGS9-2 may act as a positive or negative modulator of MOR-mediated behavioral responses in mice depending on the agonist administered. Paralleling these findings we use coimmunoprecipitation assays to show that the signaling complexes formed between RGS9-2 and Gα subunits in striatum are determined by the MOR agonist, and we identify RGS9-2 containing complexes associated with analgesic tolerance. In striatum, MOR activation promotes the formation of complexes between RGS9-2 and several Gα subunits, but morphine uniquely promotes an association between RGS9-2 and Gαi3. In contrast, RGS9-2/Gαq complexes assemble after acute application of several MOR agonists but not after morphine application. Repeated morphine administration leads to the formation of distinct complexes, which contain RGS9-2, Gβ5, and Gαq. Finally, we use simple pharmacological manipulations to disrupt RGS9-2 complexes formed during repeated MOR activation to delay the development of analgesic tolerance to morphine. Our data provide a better understanding of the brain-region-specific signaling events associated with opiate analgesia and tolerance and point to pharmacological approaches that can be readily tested for improving chronic analgesic responsiveness.
authors.affiliation: Department of Pharmacology, University of Crete Faculty of Medicine, 71003 Heraklion, Greece.
authors.forename: Kassi
authors.initials: K
authors.lastname: Psifogeorgou
authors.forename: Kassi
authors.initials: K
authors.lastname: Psigfogeorgou
authors.forename: Dimitra
authors.initials: D
authors.lastname: Terzi
authors.forename: Maria Martha
authors.initials: MM
authors.lastname: Papachatzaki
authors.forename: Artemis
authors.initials: A
authors.lastname: Varidaki
authors.forename: Deveroux
authors.initials: D
authors.lastname: Ferguson
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Gold
authors.forename: Venetia
authors.initials: V
authors.lastname: Zachariou
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000235:genetics / Q000502:physiology; D015153:Blotting, Western; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D004361:Drug Tolerance; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D054799:Phospholipase C beta / Q000378:metabolism; D010766:Phosphorylation; D020710:RGS Proteins / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D017450:Receptors, Opioid, mu / Q000819:agonists / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000071557:beta-Arrestins
chemical_list: D000701:Analgesics, Opioid; D019390:Arrestins; D020710:RGS Proteins; D017450:Receptors, Opioid, mu; D000071557:beta-Arrestins; C116925:regulator of g-protein signaling 9; D009020:Morphine; D048049:Extracellular Signal-Regulated MAP Kinases; D054799:Phospholipase C beta; D043802:GTP-Binding Protein alpha Subunits, Gq-G11