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  1. Home
  3. Gtp Release-selective Agonists Prolong Opioid Analgesic Efficacy.
  1. Home
  3. Gtp Release-selective Agonists Prolong Opioid Analgesic Efficacy.

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GTP release-selective agonists prolong opioid analgesic efficacy.

Edward L Stahl1, Matthew A Swanson2,3, Vuong Q Dang4

  • 1Department of Molecular Pharmacology and Physiology, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. EStahl@usf.edu.

Nature
|December 17, 2025

View abstract on PubMed

Summary
This summary is machine-generated.

G-protein-coupled receptors (GPCRs) can promote GTP release, not just binding. Certain agonists selectively trigger GTP release, potentially separating pain relief from side effects.

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Area of Science:

  • Pharmacology
  • Molecular Biology
  • Neuroscience

Background:

  • G-protein-coupled receptors (GPCRs) function as guanine nucleotide exchange factors (GEFs).
  • GPCRs facilitate heterotrimeric G protein activation by GDP/GTP exchange.
  • This GEF activity is not limited to promoting GTP binding.

Purpose of the Study:

  • To investigate state-selective agonist affinities for GPCRs.
  • To determine if agonists can preferentially promote GTP release over GTP binding.
  • To explore the in vivo physiological consequences of such selective agonists.

Main Methods:

  • Assessed state-selective affinities of mu opioid receptor agonists.
  • Identified agonists with preference for promoting GTP release.
  • Administered release-preferring agonists in mice to evaluate antinociceptive and physiological effects.

    • Main Results:

    • Identified mu opioid receptor agonists with state-selective affinity for promoting GTP release.
    • Two agonists demonstrated a marked preference for promoting GTP release.
    • In mice, release-preferring agonists enhanced and prolonged antinociception without increasing respiratory or cardiac side effects.

    Conclusions:

    • Agonist active-state selectivity may dictate the direction of GPCR GEF function.
    • This selectivity could influence receptor-effector engagement kinetics and specificity.
    • Potential for disentangling multifaceted drug-induced physiological responses, such as separating analgesia from adverse effects.