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Gene Review

NPFF  -  neuropeptide FF-amide peptide precursor

Homo sapiens

Synonyms: FMRFAL, FMRFamide-related peptides, Pro-FMRFamide-related neuropeptide FF
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Disease relevance of NPFF

  • To elucidate the mechanism of the cellular antiopioid activity of neuropeptide FF (NPFF), we have transfected the SH-SY5Y neuroblastoma cell line, which expresses mu-and delta-opioid receptors, with the human NPFF2receptor [1].
  • Reverse-phase high pressure liquid chromatography (HPLC) fractions of a human with normal pressure hydrocephalus cerebrospinal fluid (CSF), co-migrating with NPFF-related synthetic peptides, were characterized by capillary HPLC coupled on-line to nanospray ion trap tandem mass spectrometry [2].
  • However, another antagonist dansyl-Pro-Gln-Arg-NH(2) produced a significant drop of the mean arterial pressure only at a large dose (10mumol/kg body weight), but reversal of the NPFF-induced hypertension was modest [3].
  • These findings provide a cellular and anatomic basis for the NPFF-induced inhibition of vasopressin release has been reported consequent to hypovolemia and hyperosmolar stimulation [4].

Psychiatry related information on NPFF


High impact information on NPFF

  • Neuropeptide FF (NPFF) has been proposed to play a role in pain modulation, opioid tolerance, and several other physiological processes [6].
  • This compound does not show any effects by itself but can block efficiently the increase in blood pressure and heart rate evoked by NPFF [6].
  • Neuropeptide FF (NPFF) and neuropeptide AF (NPAF) are two mammalian amidated neuropeptides which are highly concentrated in the posterior pituitary, spinal cord, hypothalamus and medulla [7].
  • This is supported by lack of NPFF in the pituitary gland of vasopressin-deficient Brattleboro rats [7].
  • These findings and the observed increase in NPFF-immunoreactivity in the cerebrospinal fluid during development of opiate tolerance render NPFF an interesting and challenging target of investigation [7].

Biological context of NPFF


Anatomical context of NPFF

  • The central nervous system octapeptide, neuropeptide FF (NPFF), is believed to play a role in pain modulation and opiate tolerance [8].
  • NPY Y(1) antagonist BIBP3226 and mixed Y(1) antagonist/Y(4) agonist GR231118 are able to displace with low affinity, 50 -- 100 nM, the specific binding on NPFF receptors expressed in CHO cells as well as in rat dorsal spinal cord, an affinity however superior to those determined against Y(2), Y(4) or Y(5) receptors [13].
  • Within the hypothalamus of both species, dense NPFF innervation was observed in the perinuclear zone of the supraoptic nucleus (SO) just dorsolateral to the VP-positive neurons [14].
  • Semiquantitative analysis revealed that the densities of NPFF cells and fibers in many forebrain nuclei in the human correlate well with those observed for the same structures in the rat [14].
  • Extensive NPFF innervation of ventricular ependyma and brain microvasculature were common for both species [14].

Associations of NPFF with chemical compounds

  • Furthermore, BIBP3226 which is unable to inhibit the forskolin-stimulated cyclic AMP production mediated by NPFF(2) receptors, antagonizes the effect of NPFF, revealing the first antagonist of NPFF receptors [13].
  • Our results suggest that this assay, which relies on the use of a europium-labeled GTP analogue, Eu-GTP, provides a powerful alternative to the [35S]guanosine-5'-O-(3-thio)triphosphate binding assay for assessing the functional properties of NPFF analogs [15].
  • The NPFF analog [D-Tyr1, (NMe)Phe3]NPFF (1DMe) did not modify the binding parameters of the mu- and delta-specific agonists [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin and deltorphin-I, respectively [1].
  • Immunohistochemical distribution patterns of neuropeptide FF (NPFF) and neuropeptide tyrosine (NPY) were studied in the brain of rats submitted to two different protocols of heroin treatment [16].
  • In conclusion, our experiments indicated that NPFF attenuated the acute morphine locomotion and the expression of sensitization to locomotion [5].

Other interactions of NPFF

  • Using heterologous expression of ASIC subunits in Xenopus oocytes, we show here that the biphasic response of heteromeric rat and human ASIC2A+3 subtypes to low pH is selectively modulated by the neuropeptide FF (NPFF) and by the related peptide FMRFamide [9].
  • CCK- and NPFF-related drugs have potential therapeutic interest as adjuncts to opioids for alleviating pain and/or for the treatment of opioid abuse [17].
  • The ECT also stimulated a NPFF secretion peak that came approximately 5 min after ECT stimulus and preceded the prolactin peak [18].

Analytical, diagnostic and therapeutic context of NPFF

  • Reversed-phase high pressure liquid chromatography (HPLC) followed by RIA using two different antisera for NPFF showed that plasma NPFF eluted in a position identical to that of synthetic NPFF [19].
  • In order to examine whether neuropeptide FF (NPFF), an octapeptide with pain-modulating and blood pressure-raising properties in the rat, is present in circulating human blood, a radioimmunoassay (RIA) was established [19].
  • Following intracerebral ventricular administration, a NPVF-derived peptide blocked morphine-induced analgesia more potently than NPFF in both acute and inflammatory models of pain [20].
  • The promoter activity was directly comparable with the level of endogenous NPFF mRNA as determined by real-time quantitative RT-PCR [12].
  • Intracerebroventricular application of NPFF resulted in an activation of GABAergic neurons located adjacent to the PVN as revealed by immunohistochemistry for Fos protein and in situ hybridization for glutamic acid decarboxylase (GAD(67)) mRNA [4].


  1. Neuropeptide FF (NPFF) analogs functionally antagonize opioid activities in NPFF2 receptor-transfected SH-SY5Y neuroblastoma cells. Mollereau, C., Mazarguil, H., Zajac, J.M., Roumy, M. Mol. Pharmacol. (2005) [Pubmed]
  2. Identification of neuropeptide FF-related peptides in human cerebrospinal fluid by mass spectrometry. Burlet-Schiltz, O., Mazarguil, H., Sol, J.C., Chaynes, P., Monsarrat, B., Zajac, J.M., Roussin, A. FEBS Lett. (2002) [Pubmed]
  3. Cardiovascular effects of neuropeptide FF antagonists. Prokai, L., Zharikova, A.D., Juhasz, A., Prokai-Tatrai, K. Peptides (2006) [Pubmed]
  4. Neuropeptide FF (NPFF) control of magnocellular neurosecretory cells of the rat hypothalamic paraventricular nucleus (PVN). Jhamandas, J.H., Mactavish, D., Harris, K.H. Peptides (2006) [Pubmed]
  5. The role of neuropeptide FF (NPFF) in the expression of sensitization to hyperlocomotor effect of morphine and ethanol. Kotlinska, J., Pachuta, A., Dylag, T., Silberring, J. Neuropeptides (2007) [Pubmed]
  6. RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia. Simonin, F., Schmitt, M., Laulin, J.P., Laboureyras, E., Jhamandas, J.H., MacTavish, D., Matifas, A., Mollereau, C., Laurent, P., Parmentier, M., Kieffer, B.L., Bourguignon, J.J., Simonnet, G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  7. Neuropeptide FF, a mammalian neuropeptide with multiple functions. Panula, P., Aarnisalo, A.A., Wasowicz, K. Prog. Neurobiol. (1996) [Pubmed]
  8. Identification and characterization of two G protein-coupled receptors for neuropeptide FF. Bonini, J.A., Jones, K.A., Adham, N., Forray, C., Artymyshyn, R., Durkin, M.M., Smith, K.E., Tamm, J.A., Boteju, L.W., Lakhlani, P.P., Raddatz, R., Yao, W.J., Ogozalek, K.L., Boyle, N., Kouranova, E.V., Quan, Y., Vaysse, P.J., Wetzel, J.M., Branchek, T.A., Gerald, C., Borowsky, B. J. Biol. Chem. (2000) [Pubmed]
  9. Selective modulation of heteromeric ASIC proton-gated channels by neuropeptide FF. Catarsi, S., Babinski, K., Séguéla, P. Neuropharmacology (2001) [Pubmed]
  10. The high throughput screening of neuropeptide FF2 receptor ligands from Korean herbal plant extracts. Do, E.U., Piao, L.Z., Choi, G., Choi, Y.B., Kang, T.M., Shin, J., Chang, Y.J., Nam, H.Y., Kim, H.J., Kim, S.I. Peptides (2006) [Pubmed]
  11. Pulsatile secretion of neuropeptide FF into human blood. Sundblom, D.M., Hyrkkö, A., Fyhrquist, F. Peptides (1998) [Pubmed]
  12. Analysis of human neuropeptide FF gene expression. Nystedt, J.M., Brandt, A.M., Mandelin, J., Vilim, F.S., Ziff, E.B., Panula, P. J. Neurochem. (2002) [Pubmed]
  13. Agonist and antagonist activities on human NPFF(2) receptors of the NPY ligands GR231118 and BIBP3226. Mollereau, C., Gouardères, C., Dumont, Y., Kotani, M., Detheux, M., Doods, H., Parmentier, M., Quirion, R., Zajac, J.M. Br. J. Pharmacol. (2001) [Pubmed]
  14. Neuropeptide FF distribution in the human and rat forebrain: a comparative immunohistochemical study. Goncharuk, V.D., Buijs, R.M., Mactavish, D., Jhamandas, J.H. J. Comp. Neurol. (2006) [Pubmed]
  15. Assessing activation of the human neuropeptide FF2 receptor with a non-radioactive GTP binding assay. Engström, M., Närvänen, A., Savola, J.M., Wurster, S. Peptides (2004) [Pubmed]
  16. Changes in neuropeptide FF and NPY immunohistochemical patterns in rat brain under heroin treatment. D'Este, L., Casini, A., Pontieri, F.E., Renda, T.G. Brain Res. (2006) [Pubmed]
  17. Opioid and anti-opioid peptides. Cesselin, F. Fundamental & clinical pharmacology. (1995) [Pubmed]
  18. Blood concentrations of vasopressin, neuropeptide FF and prolactin are increased by high-dose right unilateral ECT. Sundblom, D.M., Heikman, P., Naukkarinen, H., Fyhrquist, F. Peptides (1999) [Pubmed]
  19. Neuropeptide FF-like immunoreactivity in human plasma. Sundblom, D.M., Panula, P., Fyhrquist, F. Peptides (1995) [Pubmed]
  20. Identification and characterization of novel mammalian neuropeptide FF-like peptides that attenuate morphine-induced antinociception. Liu, Q., Guan, X.M., Martin, W.J., McDonald, T.P., Clements, M.K., Jiang, Q., Zeng, Z., Jacobson, M., Williams, D.L., Yu, H., Bomford, D., Figueroa, D., Mallee, J., Wang, R., Evans, J., Gould, R., Austin, C.P. J. Biol. Chem. (2001) [Pubmed]
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