TY - JOUR T1 - A Unique Role of RGS9-2 in the Striatum as a Positive or Negative Regulator of Opiate Analgesia JF - The Journal of Neuroscience JO - J. Neurosci. SP - 5617 LP - 5624 DO - 10.1523/JNEUROSCI.4146-10.2011 VL - 31 IS - 15 AU - Kassi Psigfogeorgou AU - Dimitra Terzi AU - Maria Martha Papachatzaki AU - Artemis Varidaki AU - Deveroux Ferguson AU - Stephen J. Gold AU - Venetia Zachariou Y1 - 2011/04/13 UR - http://www.jneurosci.org/content/31/15/5617.abstract N2 - 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. ER -