A novel G protein‐biased agonist at the μ opioid receptor induces substantial receptor desensitisation through G protein‐coupled receptor kinase

摘要: Background and purpose G protein-biased μ opioid receptor agonists have the potential to induce less desensitisation tolerance than balanced opioids. Here, we investigated if cyclic endomorphin analogue Tyr-c[D-Lys-Phe-Tyr-Gly] (Compound 1) is a agonist characterised its ability rapid in mammalian neurones. Experimental approach The signalling trafficking properties of opioids were using bioluminescence resonance energy transfer assays, enzyme-linked immunosorbent assay phosphosite-specific immunoblotting human embryonic kidney 293 cells. Desensitisation opioid-induced currents studied rat locus coeruleus neurones whole-cell patch-clamp electrophysiology. mechanism Compound 1-induced was probed kinase inhibitors. Key results 1 has similar intrinsic activity for protein as morphine. As predicted agonist, induced minimal agonist-induced internalisation phosphorylation at intracellular serine/threonine residues known be involved protein-coupled (GRK)-mediated desensitisation. However, robust neurons, greater degree extent unaffected by activation or inhibition C (PKC) but significantly reduced GRK. Conclusion implications novel that induces substantial neurons. Surprisingly, demonstrated GRK dependent despite bias. Our findings refute assumption will evade tolerance.