New Breakthroughs in the Regulation of G-Protein Signaling: Implications in Mu and Delta Opioid Receptor-Mediated Analgesia

Abstract

The present understanding of opioid pharmacology has been influenced by discoveries relating to the mechanisms that operate on G-protein-coupled receptor (GPCR) signaling. Over the last decade, new concepts have been gradually substantiated, such as receptor preference for the regulation of certain classes of G-proteins in cells, agonists’ selection of G-protein classes for internalizing their effects, and the regulation of the functional state of Gα subunits and Gβγ dimers shuttling between activated receptors and effectors during agonist signal propagation. Current research is providing new information on how transduction regulated by mu and delta receptors influences the analgesic efficacy of their agonists. This includes aspects such as the Gβγ binding phosducin-like proteins (PhLP) and the Gα-GTP binding regulators of G-protein signaling (RGS) proteins. These regulatory proteins emerge as being involved in controlling opioid receptor phosphorylation uncoupling, modulating the potency and duration of agonist analgesic effects, and the development of tachyphylaxis and acute tolerance to opioid analgesia.