Neuropeptide FF receptor type 1 (NPFFR1)

Neuropeptide FF receptor type 1 (NPFFR1) is a Class A G protein-coupled receptor primarily expressed in the central nervous system, particularly within the hypothalamus and limbic system (UniProt Q9GZQ6). It serves as a high-affinity receptor for RF-amide neuropeptides, including Neuropeptide FF (NPFF) and RF-amide related peptides (RFRPs) (Guide to Pharmacology). NPFFR1 is fundamentally involved in the modulation of pain, where it often acts as an anti-opioid system that counteracts the effects of morphine and contributes to opioid tolerance and withdrawal (PubMed 32673481). Beyond nociception, the receptor plays a critical role in neuroendocrine regulation, specifically the hypothalamic-pituitary-gonadal axis, and influences cardiovascular functions such as blood pressure and heart rate (GeneCards). It is also implicated in the regulation of food intake, stress responses, and thermoregulation (PubMed 20803521). Pharmacological targeting of NPFFR1 with antagonists like RF9 has shown potential in preventing opioid-induced hyperalgesia and managing metabolic or anxiety disorders (Guide to Pharmacology). However, therapeutic development faces challenges due to potential cardiovascular side effects and interference with reproductive health (PubMed 11025660). The receptor primarily signals through the Gi/Go pathway to inhibit adenylyl cyclase, though it can also engage Gq-mediated calcium signaling in certain contexts (UniProt Q9GZQ6).

Other names

G-protein coupled receptor 147GPR147NPFF1RFamide-related peptide receptor OT7T022GnIH-RGonadotropin-inhibitory hormone receptorGnIH-R/RFRP-3

NPFFR1 primarily couples to Gi/Go proteins to inhibit adenylyl cyclase activity, resulting in decreased intracellular cAMP levels and the subsequent modulation of protein kinase A (PKA) and mitogen-activated protein kinase (MAPK) signaling pathways (UniProt Q9GZQ6, Guide to Pharmacology). It can also activate the phosphatidylinositol-calcium second messenger system via Gq proteins in specific cellular environments (UniProt Q9GZQ6).