Neuropeptide FF receptor (NPFFR)

The Neuropeptide FF receptor (NPFFR) family consists of two G protein-coupled receptors, NPFF1 (GPR147) and NPFF2 (GPR74), which are primarily expressed in the central nervous system and play a critical role in modulating pain and opioid signaling (UniProt, Q9GZQ6; UniProt, Q9Y5Y0). These receptors are activated by RF-amide peptides, such as Neuropeptide FF (NPFF) and Neuropeptide AF (NPAF), and are known for their "anti-opioid" properties, often counteracting the analgesic effects of morphine (PubMed, PMID: 16431083). Beyond nociception, NPFF receptors are involved in cardiovascular regulation, neuroendocrine function, and the control of food intake (IUPHAR/BPS Guide to Pharmacology). In disease contexts, they are significant targets for managing chronic pain and opioid-induced hyperalgesia, as well as potential targets for metabolic disorders like obesity (PubMed, PMID: 22464924). Pharmacological modulation of NPFF receptors, particularly through antagonists like RF9, is being explored to enhance opioid analgesia and prevent the development of opioid tolerance (PubMed, PMID: 16766524). However, their broad expression and involvement in multiple physiological systems present challenges regarding cardiovascular and systemic safety.

Other names

G-protein coupled receptor 147 (GPR147)G-protein coupled receptor 74 (GPR74)NPFF1 receptorNPFF2 receptorRFamide receptorNeuropeptide FF receptor 1Neuropeptide FF receptor 2

Ligand binding to NPFF receptors triggers G protein-mediated signaling, primarily through Gi/o proteins, leading to the inhibition of adenylyl cyclase and the modulation of ion channels to regulate neuronal excitability and neurotransmitter release (IUPHAR/BPS Guide to Pharmacology; UniProt).