Neuropeptide FF

Processing

Processing of the NPFFA precursor at basic proteolytic sites generates a NPFF-containing peptide with three additional N-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 for RFamide-related peptides (RFRPs, also called GnIH for gonadotropin 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.

Function

Neuropeptide FF (NPFF) and several other RFamide related peptides issued from two precursors, interact with varying affinity with two subtypes of G protein-coupled receptors, namely NPFF1 and NPFF2 subtypes and are involved in several physiological functions such as cardiovascular regulation, hormonal control, macrophage activation, body temperature homeostasis and pain modulation.

NPFF and opioid 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.

As well as affecting pain perception, NPFF also modulates related processes such as inflammation and macrophage activation, and neurogenesis during recovery from brain injury, as well as being linked to mood disorders such as depression and anxiety. Peripheral NPFF receptors are also involved in the regulation of blood pressure.

NPFF also controls the number and metabolic effects of adipose tissue macrophages, and NPFF is necessary for adipose tissue health, but over-activation of NPFFR2 receptors has been linked to obesity and metabolic syndrome.

References

References

1. (June 1997). "A human gene encoding morphine modulating peptides related to NPFF and FMRFamide". FEBS Letters.
2. "Entrez Gene: NPFF neuropeptide FF-amide peptide precursor".
3. (2025). "Structural insights into the selective recognition of RF-amide peptides by neuropeptide FF receptor 2". EMBO Reports.
4. (2025). "Structural basis of peptide recognition and modulation for neuropeptide FF receptors". Cell Reports.
5. (2020). "Crosstalk between Opioid and Anti-Opioid Systems: An Overview and Its Possible Therapeutic Significance". Biomolecules.
6. (2020). "Neuropeptide FF and Its Receptors: Therapeutic Applications and Ligand Development". Journal of Medicinal Chemistry.
7. (2025). "The dual modulating effects of neuropeptide FF on morphine-induced analgesia at the spinal level". Neuroscience.
8. (2021). "Non-Opioid Peptides Targeting Opioid Effects". International Journal of Molecular Sciences.
9. (2024). "Modulatory role of neuropeptide FF system in macrophages". Peptides.
10. (2024). "Neuropeptide FF Promotes Neuronal Survival and Enhances Synaptic Protein Expression Following Ischemic Injury". International Journal of Molecular Sciences.
11. (2024). "Brain RFamide Neuropeptides in Stress-Related Psychopathologies". Cells.
12. (2024). "An Overview on Renal and Central Regulation of Blood Pressure by Neuropeptide FF and Its Receptors". International Journal of Molecular Sciences.
13. (June 2017). "Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages". The Journal of Clinical Investigation.
14. (September 2025). "Neuropeptide FF Receptor 2 Overexpression Aggravates Lipid Accumulation and Metabolic Dysfunction in Mice with Diet-Induced Metabolic Stress". Biomedical Journal.