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Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):E2085-E2094. doi: 10.1073/pnas.1707887115. Epub 2018 Feb 12.

Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway.

Author information

1
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
2
Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
3
Department of Basic Sciences, University of Crete Medical School, 71003 Heraklion, Greece.
4
Gene Delivery Technology Core, Massachusetts General Hospital, MA 01239.
5
Cure Huntington's Disease Initiative (CHDI) Foundation, Princeton, NJ 08540.
6
Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
7
Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
8
Green Center for Systems Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
9
Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029; venetia.zachariou@mssm.edu.

Abstract

Regulator of G protein signaling z1 (RGSz1), a member of the RGS family of proteins, is present in several networks expressing mu opioid receptors (MOPRs). By using genetic mouse models for global or brain region-targeted manipulations of RGSz1 expression, we demonstrated that the suppression of RGSz1 function increases the analgesic efficacy of MOPR agonists in male and female mice and delays the development of morphine tolerance while decreasing the sensitivity to rewarding and locomotor activating effects. Using biochemical assays and next-generation RNA sequencing, we identified a key role of RGSz1 in the periaqueductal gray (PAG) in morphine tolerance. Chronic morphine administration promotes RGSz1 activity in the PAG, which in turn modulates transcription mediated by the Wnt/β-catenin signaling pathway to promote analgesic tolerance to morphine. Conversely, the suppression of RGSz1 function stabilizes Axin2-Gαz complexes near the membrane and promotes β-catenin activation, thereby delaying the development of analgesic tolerance. These data show that the regulation of RGS complexes, particularly those involving RGSz1-Gαz, represents a promising target for optimizing the analgesic actions of opioids without increasing the risk of dependence or addiction.

KEYWORDS:

G proteins; RNA sequencing; analgesia; morphine; periaqueductal gray

PMID:
29440403
PMCID:
PMC5834666
DOI:
10.1073/pnas.1707887115
[Indexed for MEDLINE]
Free PMC Article

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