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

Kassi Psigfogeorgou, Dimitra Terzi, Maria Martha Papachatzaki, Artemis Varidaki, Deveroux Ferguson, Stephen J. Gold, Venetia Zachariou

Research output: Contribution to journalArticle

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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 Got 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 Gai3. 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, Gjβ5, 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.

Original languageEnglish (US)
Pages (from-to)5617-5624
Number of pages8
JournalJournal of Neuroscience
Volume31
Issue number15
DOIs
StatePublished - Apr 13 2011
Externally publishedYes

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Opiate Alkaloids
Analgesia
Morphine
Analgesics
Pharmacology
Opioid Receptors
G-Protein-Coupled Receptors
Brain

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Psigfogeorgou, K., Terzi, D., Papachatzaki, M. M., Varidaki, A., Ferguson, D., Gold, S. J., & Zachariou, V. (2011). A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia. Journal of Neuroscience, 31(15), 5617-5624. https://doi.org/10.1523/JNEUROSCI.4146-10.2011

A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia. / Psigfogeorgou, Kassi; Terzi, Dimitra; Papachatzaki, Maria Martha; Varidaki, Artemis; Ferguson, Deveroux; Gold, Stephen J.; Zachariou, Venetia.

In: Journal of Neuroscience, Vol. 31, No. 15, 13.04.2011, p. 5617-5624.

Research output: Contribution to journalArticle

Psigfogeorgou, K, Terzi, D, Papachatzaki, MM, Varidaki, A, Ferguson, D, Gold, SJ & Zachariou, V 2011, 'A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia', Journal of Neuroscience, vol. 31, no. 15, pp. 5617-5624. https://doi.org/10.1523/JNEUROSCI.4146-10.2011
Psigfogeorgou, Kassi ; Terzi, Dimitra ; Papachatzaki, Maria Martha ; Varidaki, Artemis ; Ferguson, Deveroux ; Gold, Stephen J. ; Zachariou, Venetia. / A unique role of RGS9-2 in the striatum as a positive or negative regulator of opiate analgesia. In: Journal of Neuroscience. 2011 ; Vol. 31, No. 15. pp. 5617-5624.
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