Beyond receptor identity: context-dependent GPCR targeting for pain and itch

G protein-coupled receptors (GPCRs) are among the most tractable targets in pain and itch, yet receptor identity and G-protein coupling alone do not reliably predict the sensory effects or therapeutic window of a GPCR-targeted drug. These outcomes also depend on the cell type that expresses the receptor, the anatomical compartment in which it is activated, the subcellular pool from which it signals, and the local availability of its endogenous ligands. With these factors in mind, we compare five approaches to improving therapeutic selectivity: restricting drug exposure, exploiting disease-associated microenvironments, enhancing endogenous signaling through allosteric modulation, distinguishing signaling bias from intrinsic efficacy, and targeting engineered receptors through chemogenetics. Examples include peripherally restricted opioids such as difelikefalin, a kappa agonist approved for pruritus in patients on hemodialysis, pH-dependent agonists that preferentially activate receptors under acidic conditions, and chemogenetic actuators with limited brain penetration. Receptor-level pharmacology remains the necessary starting point, but it is more informative when considered alongside the determinants that the chosen strategy is designed to control, an approach illustrated mainly by preclinical pain studies, with randomized clinical evidence for itch provided by difelikefalin.