Pain is a widespread and persistent public health problem with myriad socio-economic ramifications, including addiction and opiate use disorders. Many therapeutics used for pain management today have their origins in plants, from aspirin to opiates. Still, most plant derived compounds have not been studied extensively for their bioactivity, including many that are synthesized by medicinal plants. This application is submitted to PA-18-591 in response to NOT-TR-20-008, a call for studies to characterize understudied proteins in the druggable human genome with the potential to serve as new targets for the treatment of pain. We propose to establish a rapid research pipeline for linking plant-derived compounds to nociception (pain) and to GPCRs and ion channels in the druggable human genome. As more than 80% of these membrane proteins are conserved in C. elegans and this model organism is a proven platform for phenotypic screens, we propose screens for compounds and genes affecting nociception as well as to identify novel ligand-receptor pairs using C. elegans nematodes. We will first link plant-derived compounds to modulation of thermal nociceptors and then to determine which of the understudied, but conserved GPCRs and ion channels are involved in nociception in the presence or absence of entry point compounds (Aim 1) and next exploit the fact that C. elegans chemosensory neurons express multiple GPCRs and that activation of these receptors causes either attraction or repulsion behaviors (Aim 2). This innovative research project has the potential to determine the function of the specified genes in nociception and to reveal novel ligand-receptor pairs that could serve as new entry points for improved or alternative pain treatments.