A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia

J Neurosci. 2011 Apr 13;31(15):5617-24. doi: 10.1523/JNEUROSCI.4146-10.2011.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Animals
  • Arrestins / genetics
  • Arrestins / physiology
  • Blotting, Western
  • Corpus Striatum / drug effects
  • Corpus Striatum / physiology*
  • Drug Tolerance
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / physiology
  • GTP-Binding Protein alpha Subunits, Gq-G11 / genetics
  • GTP-Binding Protein alpha Subunits, Gq-G11 / metabolism
  • Immunoprecipitation
  • Mice
  • Mice, Knockout
  • Morphine / pharmacology
  • Phospholipase C beta / metabolism
  • Phosphorylation
  • RGS Proteins / drug effects
  • RGS Proteins / genetics
  • RGS Proteins / physiology*
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / genetics
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • beta-Arrestins


  • Analgesics, Opioid
  • Arrestins
  • RGS Proteins
  • Receptors, Opioid, mu
  • beta-Arrestins
  • regulator of g-protein signaling 9
  • Morphine
  • Extracellular Signal-Regulated MAP Kinases
  • Phospholipase C beta
  • GTP-Binding Protein alpha Subunits, Gq-G11