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

Sevasti Gaspari, Immanuel Purushothaman, Valeria Cogliani, Farhana Sakloth, Rachael L. Neve, David Howland, Robert H. Ring, Elliott M. Ross, Li Shen, Venetia Zachariou

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 ofmorphine 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.

Original languageEnglish (US)
Pages (from-to)E2085-E2094
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number9
DOIs
StatePublished - Feb 27 2018

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GTP-Binding Protein Regulators
Catenins
Wnt Signaling Pathway
Opioid Analgesics
Morphine
Analgesics
Periaqueductal Gray
mu Opioid Receptor
RGS Proteins
RNA Sequence Analysis
Genetic Models
Membranes
Brain

Keywords

  • Analgesia
  • G proteins
  • Morphine
  • Periaqueductal gray
  • RNA sequencing

ASJC Scopus subject areas

  • General

Cite this

Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway. / Gaspari, Sevasti; Purushothaman, Immanuel; Cogliani, Valeria; Sakloth, Farhana; Neve, Rachael L.; Howland, David; Ring, Robert H.; Ross, Elliott M.; Shen, Li; Zachariou, Venetia.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 9, 27.02.2018, p. E2085-E2094.

Research output: Contribution to journalArticle

Gaspari, Sevasti ; Purushothaman, Immanuel ; Cogliani, Valeria ; Sakloth, Farhana ; Neve, Rachael L. ; Howland, David ; Ring, Robert H. ; Ross, Elliott M. ; Shen, Li ; Zachariou, Venetia. / Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin pathway. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 9. pp. E2085-E2094.
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