NPFFR1

NPFFR1 (neuropeptide FF receptor 1, GPR147) is a class A G protein-coupled receptor that functions as a receptor for the RF-amide neuropeptides NPFF and NPAF and mediates neuropeptide signaling through Gi/o-dependent pathways^[1][2]. Mechanistically, NPFFR1 participates in neuropeptide signaling networks that regulate nociception, opioid responsiveness, hormonal modulation, thermoregulation, and metabolic homeostasis, linking extracellular RF-amide peptides to intracellular signaling programs^[3][4]. Structural studies further demonstrated that NPFFR1 and NPFFR2 share conserved RF-amide peptide recognition mechanisms while exhibiting subtype-specific determinants of ligand selectivity and G-protein coupling, providing a molecular basis for distinct biological functions^[3]. In disease-relevant and pharmacological models, the NPFF system has been strongly associated with pain regulation, opioid tolerance, opioid dependence, and metabolic disorders, making NPFFR1 an important target for mechanistic studies of neuropeptide-mediated signaling^[4][3]. Compared with the related isoform NPFFR2, NPFFR1 is broadly distributed throughout the central nervous system, particularly in limbic and hypothalamic regions, whereas NPFFR2 is more prominently associated with spinal nociceptive circuits, highlighting functional specialization between the receptor subtypes^[5]. For experimental applications, endogenous RFamide-related peptides, including RFRP-derived ligands, activate NPFFR1, while subtype-selective antagonists have been developed to dissect NPFFR1-dependent regulation of reproduction, stress responses, anxiety-related behaviors, and opioid-associated signaling pathways^[6].