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Suppression of RGSz1 function optimizes the actions of opioid analgesics by mechanisms that involve the Wnt/β-catenin
Sevasti Gaspari1,2,3, Immanuel Purushothaman1,2, Valeria Cogliani1,2
1Fishberg Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029.
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.
Insights
Regulator of G protein signaling z1 (RGSz1) suppression enhances opioid pain relief and delays tolerance by modulating Wnt/β-catenin signaling. This discovery offers a new target for optimizing analgesia without addiction risks.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Regulator of G protein signaling z1 (RGSz1) is implicated in mu opioid receptor (MOPR) signaling networks.
- Understanding RGSz1's role is crucial for developing safer opioid analgesics.
Purpose of the Study:
- To investigate the role of RGSz1 in opioid analgesia, tolerance, and associated side effects.
- To identify molecular mechanisms by which RGSz1 influences morphine response.
Main Methods:
- Utilized genetic mouse models with altered RGSz1 expression (global and brain region-specific).
- Employed biochemical assays and next-generation RNA sequencing.
- Focused on the periaqueductal gray (PAG) region.
Main Results:
- Suppression of RGSz1 function improved MOPR agonist analgesic efficacy in male and female mice.
- Reduced RGSz1 activity delayed morphine tolerance development and decreased sensitivity to rewarding/locomotor effects.
- RGSz1 in the PAG modulates Wnt/β-catenin signaling to promote morphine analgesic tolerance.
Conclusions:
- RGSz1 activity in the PAG is a key mediator of morphine analgesic tolerance.
- Targeting RGSz1 complexes, specifically RGSz1-Gαz, offers a promising strategy for optimizing opioid analgesia.
- Modulating RGSz1 may lead to improved pain management with reduced risks of dependence and addiction.
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