Novel Ligands for the Orphan Receptor <scp>GPR151</scp> Modulate Morphine Action

S]-GTPγS binding assay. Both ligands induced GPR151 internalization and increased reporter gene expression in Chinese hamster ovary cells transiently expressing human GPR151 upon ligand stimulation. Activity evaluation employing structural analogs provided insights into a series of ligand structure-activity relationships. Administration of the unique ligands had no effect on thermal hyperalgesia in rats; however, an agonist and a partial agonist enhanced and attenuated the analgesic effect of morphine, respectively, when co-administered. These findings not only reveal the physiological role of GPR151 in pain transmission but also demonstrate its potential as a novel drug target for pain control. Our findings indicate that the development of GPR151 ligands can contribute to the reduction of opioid use.