Chronic pain is experienced by 1 in 5 adults during their lifetime and is often poorly managed by analgesics that are either ineffective or cause unacceptable side-effects. Hence, there is a desperate need for new analgesics that may overcome these limitations. Pain-transmitting receptors of the G Protein-Coupled Receptor (GPCR) superfamily have long been considered valuable analgesic targets, but with limited clinical success. This is well-illustrated by the Neurokinin 1 Receptor (NK1R) - a peptide receptor that can be activated by the tachykinin peptide Substance P (SP) and is known to play a central role in relaying pain signals from the periphery to the central nervous system. However, potent selective NK1R antagonists failed to show efficacy in clinical trials. The reasons remain unclear and suggest that a greater understanding of tachykinin biology is required.
NK1R is one of a growing list of GPCRs that are known to undergo endocytosis and participate in spatially-organised signalling. Using subcellularly targeted biosensors that can track real-time measurement of G protein coupling or kinase activity, this presentation highlights some of our published and recent findings investigating how NK1R assembles unique, membrane-specific signalling complexes to control downstream signalling cascades in a spatially and temporally-controlled manner. Furthermore, by developing a range of novel drug-lipid conjugates and pH-responsive nanoparticles that can promote endosomal delivery of NK1R antagonists, we have demonstrated that the NK1R-mediated “endosomal signalling axis” is functionally important and a major driver of central pain transmission in preclinical pain models. Together, we propose that some analgesic candidates may have failed due to their preference for binding cell surface GPCRs rather than internalised or “hidden” receptors, and that specialised delivery technologies are valuable tools for precisely controlling the intracellular distribution drugs and enhancing their analgesic potential.