Neuropeptide FF (NPFF, FLFQPQRFa) is a mammalian amidatedneuropeptide originally isolated from bovine brain and characterized as apain-modulating peptide, with anti-opioid activity on morphine-induced analgesia.
In humans, neuropeptide FF peptides are encoded by theNPFFgene. Two genes encoding two different receptors (NPFF1 andNPFF2) and two precursors [NPFFA (this gene) and NPFFB (NPVF)] have been cloned in several mammalian species.[5][6][7][8]
Processing of the NPFFA precursor at basic proteolytic sites generates a NPFF-containing peptide with three additionalN-terminal amino acids different between species, and a NPSF (SLAAPQRFa)-containing peptide, the length of which depends on the species. NPFFB, identified as a precursor forRFamide-related peptides (RFRPs, also called GnIH forgonadotropin inhibitory hormone), contains a LPLRFa-containing peptide and a peptide sharing with NPFF the same C-terminal PQRFamide motif, such as NPVF (VPNLPQRFa) in human.
Neuropeptide FF (NPFF) and several other RFamide related peptides issued from two precursors, interact with varying affinity with two subtypes ofG protein-coupled receptors, namely NPFF1 and NPFF2 subtypes and are involved in several physiological functions such as cardiovascular regulation, hormonal control, macrophage activation, body temperaturehomeostasis and pain modulation.[6]
NPFF andopioid systems have been shown to interact at several levels, from animal behavior to receptor molecules. Nociception is the physiological function in which this interaction has been the most extensively studied but reward, locomotion, feeding and intestinal motility are also affected.Endogenous opioids are necessary for the analgesic properties of spinally injected NPFF while endogenous NPFF peptides are involved in the process of analgesic tolerance/hyperalgesia induced by chronic opioid treatment.[9][10][11]
As well as affecting pain perception, NPFF also modulates related processes such as inflammation and macrophage activation,[12][13] andneurogenesis during recovery from brain injury,[14] as well as being linked to mood disorders such as depression and anxiety.[15] Peripheral NPFF receptors are also involved in the regulation of blood pressure.[16]
^Chen D, Zhang M, He Y, Wu S, Kuang J, Zhang Z, et al. (2025). "The dual modulating effects of neuropeptide FF on morphine-induced analgesia at the spinal level".Neuroscience.565:247–256.doi:10.1016/j.neuroscience.2024.12.010.PMID39647601.
^Wang Y, Zuo Z, Shi J, Fang Y, Yin Z, Wang Z, et al. (2024). "Modulatory role of neuropeptide FF system in macrophages".Peptides.174 171164.doi:10.1016/j.peptides.2024.171164.PMID38272240.
Laemmle B, Schindler M, Beilmann M, Hamilton BS, Doods HN, Wieland HA (March 2003). "Characterization of the NPGP receptor and identification of a novel short mRNA isoform in human hypothalamus".Regulatory Peptides.111 (1–3):21–29.doi:10.1016/S0167-0115(02)00220-3.PMID12609745.S2CID24049458.
