Researchers have developed a new highly effective therapeutic for pain relief by altering the chemical properties of an antinausea drug, netupitant. The modified drug is able to enter the intracellular membrane-bound endosome and target the GPCRs therein, rather than at the cell surface, that leads to optimal pain relief. The study, published in the Proceedings of the National Academy of Sciences (PNAS) on May 22, 2023, was led by Nigel Bunnett, Professor and Chair of Molecular Pathobiology at NYU College of Dentistry, and illustrates how GPCR-mediated pain signaling occurs inside the endosomes rather than at the surface, highlighting the need for drugs that can reach receptors within the cells itself.