• Yevgen Yudin and Tibor Rohacs.
• Department of Pharmacology, Physiology and Neuroscience, Rutgers, New Jersey Medical School, Newark, New Jersey.
• Br. J. Pharmacol. 2019 Sep 1; 176 (17): 3110-3125.

Background And PurposeOpioids remain the most efficient medications against severe pain; they act on receptors that couple to heterotrimeric G-proteins in the Gαi/o family. Opioids exert many of their acute effects through modulating ion channels via Gβγ subunits. Many of their side effects are attributed to β-arrestin recruitment. Several biased agonists that do not recruit β-arrestins, but activate G-protein-dependent pathways, have recently been developed. While these compounds have been proposed to be full agonists of G-protein signalling in several high throughput pharmacological assays, their effects were not studied on ion channel targets.Experimental ApproachHere, we used patch-clamp electrophysiology and Ca2+ imaging to test the effects of TRV130, PZM21, and herkinorin, three G-protein-biased agonists of μ-opioid receptors, on ion channel targets of Gαi/o /Gβγ signalling. We also studied G-protein dissociation using a FRET-based assay.Key ResultsAll three biased agonists induced smaller activation of G-protein-coupled inwardly rectifying K+ channels (Kir 3.2) and smaller inhibition of transient receptor potential melastatin (TRPM3) channels than the full μ receptor agonist DAMGO. Co-application of TRV130 or PZM21, but not herkinorin, alleviated the effects of DAMGO on both channels. PZM21 and TRV130 also decreased the effect of morphine on Kir 3.2 channels. The CaV 2.2 channel was also inhibited less by PZM21 and TRV130 than by DAMGO. We also found that TRV130, PZM21, and herkinorin were less effective than DAMGO at inducing dissociation of the Gαi /Gβγ complex.Conclusion And ImplicationsTRV130, PZM21, and potentially herkinorin are partial agonists of μ receptors.© 2019 The British Pharmacological Society.

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