The Neuropeptide FF receptor family contains two subtypes, NPFF1 and NPFF2 (provisional nomenclature [3]), which exhibit high affinities for neuropeptide FF (NPFF, O15130) and RFamide related peptides (RFRP: precursor gene symbol NPVF, Q9HCQ7). NPFF1 is broadly distributed in the central nervous system with the highest levels found in the limbic system and the hypothalamus. NPFF2 is present in high density in the superficial layers of the mammalian spinal cord where it is involved in nociception and modulation of opioid functions.

An orphan receptor GPR83 (Q9NYM4) shows sequence similarities with NPFF1, NPFF2, PrRP and QRFP receptors. The antagonist RF9 is selective for NPFF receptors, but does not distinguish between the NPFF1 and NPFF2 subtypes (pK_i 7.1 and 7.2, respectively, [2,13]).

* Key recommended reading is highlighted with an asterisk

* Moulédous L, Mollereau C, Zajac JM. (2010) Opioid-modulating properties of the neuropeptide FF system. Biofactors, 36 (6): 423-9. [PMID:20803521]

* Nguyen T, Marusich J, Li JX, Zhang Y. (2020) Neuropeptide FF and Its Receptors: Therapeutic Applications and Ligand Development. J Med Chem, 63 (21): 12387-12402. [PMID:32673481]

* Vyas N, Mollereau C, Chevé G, McCurdy CR. (2006) Structure-activity relationships of neuropeptide FF and related peptidic and non-peptidic derivatives. Peptides, 27 (5): 990-6. [PMID:16490282]

* Yang HY, Tao T, Iadarola MJ. (2008) Modulatory role of neuropeptide FF system in nociception and opiate analgesia. Neuropeptides, 42 (1): 1-18. [PMID:17854890]

1. Bonini JA, Jones KA, Adham N, Forray C, Artymyshyn R, Durkin MM, Smith KE, Tamm JA, Boteju LW, Lakhlani PP et al.. (2000) Identification and characterization of two G protein-coupled receptors for neuropeptide FF. J Biol Chem, 275 (50): 39324-31. [PMID:11024015]

2. Davidson JS, Assefa D, Pawson A, Davies P, Hapgood J, Becker I, Flanagan C, Roeske R, Millar R. (1997) Irreversible activation of the gonadotropin-releasing hormone receptor by photoaffinity cross-linking: localization of attachment site to Cys residue in N-terminal segment. Biochemistry, 36 (42): 12881-9. [PMID:9335546]

3. Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ. (2005) International Union of Pharmacology. XLVI. G protein-coupled receptor list. Pharmacol Rev, 57 (2): 279-88. [PMID:15914470]

4. Gouardères C, Mazarguil H, Mollereau C, Chartrel N, Leprince J, Vaudry H, Zajac JM. (2007) Functional differences between NPFF1 and NPFF2 receptor coupling: high intrinsic activities of RFamide-related peptides on stimulation of [35S]GTPgammaS binding. Neuropharmacology, 52 (2): 376-86. [PMID:17011599]

5. Gouardères C, Quelven I, Mollereau C, Mazarguil H, Rice SQ, Zajac JM. (2002) Quantitative autoradiographic distribution of NPFF1 neuropeptide FF receptor in the rat brain and comparison with NPFF2 receptor by using [125I]YVP and [(125I]EYF as selective radioligands. Neuroscience, 115 (2): 349-61. [PMID:12421602]

6. Gouardères C, Zajac JM. (2007) Biochemical anti-opioid action of NPFF2 receptors in rat spinal cord. Neurosci Res, 58 (1): 91-4. [PMID:17337079]

7. Hinuma S, Shintani Y, Fukusumi S, Iijima N, Matsumoto Y, Hosoya M, Fujii R, Watanabe T, Kikuchi K, Terao Y et al.. (2000) New neuropeptides containing carboxy-terminal RFamide and their receptor in mammals. Nat Cell Biol, 2 (10): 703-8. [PMID:11025660]

8. Lameh J, Bertozzi F, Kelly N, Jacobi PM, Nguyen D, Bajpai A, Gaubert G, Olsson R, Gardell LR. (2010) Neuropeptide FF receptors have opposing modulatory effects on nociception. J Pharmacol Exp Ther, 334 (1): 244-54. [PMID:20354177]

9. Mollereau C, Gouardères C, Dumont Y, Kotani M, Detheux M, Doods H, Parmentier M, Quirion R, Zajac JM. (2001) Agonist and antagonist activities on human NPFF(2) receptors of the NPY ligands GR231118 and BIBP3226. Br J Pharmacol, 133 (1): 1-4. [PMID:11325787]

10. Mollereau C, Mazarguil H, Marcus D, Quelven I, Kotani M, Lannoy V, Dumont Y, Quirion R, Detheux M, Parmentier M et al.. (2002) Pharmacological characterization of human NPFF(1) and NPFF(2) receptors expressed in CHO cells by using NPY Y(1) receptor antagonists. Eur J Pharmacol, 451 (3): 245-56. [PMID:12242085]

11. Mollereau C, Mazarguil H, Zajac JM, Roumy M. (2005) Neuropeptide FF (NPFF) analogs functionally antagonize opioid activities in NPFF2 receptor-transfected SH-SY5Y neuroblastoma cells. Mol Pharmacol, 67 (3): 965-75. [PMID:15608144]

12. Roussin A, Serre F, Gouardères C, Mazarguil H, Roumy M, Mollereau C, Zajac JM. (2005) Anti-analgesia of a selective NPFF2 agonist depends on opioid activity. Biochem Biophys Res Commun, 336 (1): 197-203. [PMID:16129413]

13. Simonin F, Schmitt M, Laulin JP, Laboureyras E, Jhamandas JH, MacTavish D, Matifas A, Mollereau C, Laurent P, Parmentier M et al.. (2006) RF9, a potent and selective neuropeptide FF receptor antagonist, prevents opioid-induced tolerance associated with hyperalgesia. Proc Natl Acad Sci USA, 103 (2): 466-71. [PMID:16407169]

14. Talmont F, Garcia LP, Mazarguil H, Zajac JM, Mollereau C. (2009) Characterization of two novel tritiated radioligands for labelling Neuropeptide FF (NPFF(1) and NPFF(2)) receptors. Neurochem Int, 55 (8): 815-9. [PMID:19682524]

Subcommittee members: Jean-Marie Zajac (Chairperson) Institut de Pharmacologie et de Biologie Structurale CNRS UMR 5089 205 Route de Narbonne Toulouse Cedex 31077 France Lionel Moulédous CRCA/UMR 5169 CNRS/Université Paul Sabatier 118 Route de Narbonne 31062 TOULOUSE Cedex 9 France Kazuyoshi Tsutsui Department of Biology Waseda University Center for Medical life Science of Waseda University 2-2 Wakamatsu-cho Shinjuku-ku Tokyo 162-8480 Japan Takayoshi Ubuka Room 3-3-05 Brain Research Institute Monash Sunway (BRIMS) Jeffrey Cheah School of Medicine and Health Sciences Monash University Malaysia Jalan Lagoon Selatan 47500 Bandar Sunway Selangor Darul Ehsan, Malaysia

Other contributors: Catherine Mollereau-Manaute Institut de Pharmacologie et de Biologie Structurale CNRS UMR 5089 205 Route de Narbonne Toulouse Cedex 31077 France Michel Roumy Institut de Pharmacologie et de Biologie Structurale CNRS UMR 5089 205 Route de Narbonne Toulouse Cedex 31077 France