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

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

Open Access

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

Author(s) -

Sevasti Gaspari,

Immanuel Purushothaman,

Valeria Cogliani,

Farhana Sakloth,

Rachael L. Neve,

David Howland,

Robert H. Ring,

Elliott M. Ross,

Li Shen,

Venetia Zachariou

Publication year - 2018

Publication title -

proceedings of the national academy of sciences

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 5.011

H-Index - 771

eISSN - 1091-6490

pISSN - 0027-8424

DOI - 10.1073/pnas.1707887115

Subject(s) - wnt signaling pathway , analgesic , periaqueductal gray , opioid , morphine , μ opioid receptor , pharmacology , axin2 , drug tolerance , regulator of g protein signaling , receptor , neuroscience , chemistry , signal transduction , microbiology and biotechnology , medicine , biology , g protein , central nervous system , midbrain , gtpase activating protein

Significance Opioids are used to alleviate severe pain, but their long-term use leads to analgesic tolerance, dependence, and addiction. Here, we targeted specific intracellular pathways to dissociate the analgesic actions of opioids from addiction-related effects. Using genetically modified male and female mice in models of addiction and analgesia, we revealed a key role of an intracellular modulator of the mu opioid receptor, RGSz1, in opioid actions. We applied next-generation sequencing and biochemical assays to delineate the mechanism of RGSz1 action in the mouse periaqueductal gray. Findings from this work point to novel intracellular pathways that can be targeted to optimize the actions of opioids for the treatment of chronic pain.

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