Why the study?
G protein-biased mu opioid receptor agonists may induce less receptor desensitisation and tolerance than balanced opioids, but whether the cyclic endomorphin analogue Compound 1 acts as one was unknown.
Population
Human embryonic kidney 293 cells and rat locus coeruleus neurones
Comparison
Compound 1 vs morphine and kinase inhibitors
Design
Preclinical in vitro and ex vivo pharmacological study
Key result
Compound 1 induced robust rapid μ receptor desensitisation in locus coeruleus neurons to a greater degree than morphine, demonstrating that G protein-biased agonists do not evade desensitisation.
Authors
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Challenges assumption that G protein bias evades μ-opioid desensitization; hypothesis-generating for tolerance mechanisms.
The G protein-biased μ agonist Compound 1 induces substantial GRK-dependent receptor desensitisation, challenging the assumption that biased agonists evade tolerance.
Groom et al. (2020) studied this question. Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) vs. morphine was evaluated on μ receptor desensitisation. Compound 1 induced robust rapid μ receptor desensitisation in locus coeruleus neurons to a greater degree than morphine, demonstrating that G protein-biased agonists do not evade desensitisation.
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