Morphine modulating neuroppetides have been shown to have important roles in nociception, anxiety, learning and memory, and cardiovascular reflex.

In 1985, Yang et al., described the isolation, sequencing, synthesis, and pharmacological   characterization of two brain neuropeptides that modulate the action of morphine (Phe-Met-Arg-Phe-NH2/opioids/antinociception)1. Two receptors (FF1 and FF2) have been molecularly identified for NPFF and NPAF. In 2001 Liu et al., characterized a novel gene designated NPVF that encodes two neuropeptides highly similar to NPFF. NPVF derived peptides displayed higher affinity for FF1 than NPFF-derived peptides, but showed poor agonist activity for FF2 2

Structural Characteristics
In 1985 Yang et al., found that the two neuropeptides that cross react with an antiserum raised against Phe-Met-Arg-Phe-NH2 purified from bovine brain extract. Their structures were determined to be Ala-Gly-Glu-Gly-Leu-Ser-Ser-Pro-Phe-Trp-Ser-Leu-Ala-Ala-Pro-Gln-Arg-Phe-NH2 and Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2. The sequences were determined by gas-phase sequencing, except for the COOH-terminal phenyl alanine amides. These were assigned on the basis of the reactivity of the peptides with the anti-Phe-Met-Arg-Phe-NH2 antiserum, which appears to recognize the determinant -Arg-Phe-NH2. Both peptides were synthesized, and the synthetic peptides were found to have the same HPLC retention times as the endogenous Phe-Met-Arg-Phe-NH2-immunoreactive peptides, thus confirming the assignment of phenylalaninamide to the COOH-terminal positions 1.

Mode of Action
NPFF was shown to exhibit anti-opiate activity by inhibiting a variety of morphine-induced effects. For example, NPFF opposes the anti-nociceptive properties of morphine and the development of morphine tolerance and dependence, in addition to precipating withdrawal in morphine-dependent animals. Its anti-opiate effects appear to be mediated via a single class of specific NPFF receptors, which are localized in spinal and supra spinal regions enriched with endogenous opioids. NPFF antagonizes morphine effects via binding to non-opioid (NPFF) receptors, not binding to opioid receptors 3,4


Control of pain, NPAF and NPFF play important roles in the control of pain and analgesia through interactions with the opioid system.  Intracerebroventricular administration of FMRFamide, NPFF, or NPAF attenuated morphine-induced analgesia whereas injection of antisera against FMRFamide or NPFF had the opposite effect 5.

Anti-opioid peptides, Administration of NPFF into morphine-tolerant rats induced symptoms of the withdrawal whereas administration of anti-NPFF IgG reversed morphine tolerance. Such observations led to the classification of NPFF as one type of anti-opioid peptides, which have been hypothesized to be partially responsible for the rapid development of opioid tolerance and dependence in animal models and clinical use of opioids 6.

Pro-opioid effect following intrathecal administration NPFF, ICV-administrated NPFF was able to attenuate neuropathic pain independent of the opioid system. In addition, FMRFamide and NPFF were also shown to affect the cardiovascular system and cause other behavioral changes in mammals 7.

Tail-flick latency in rats, Both of the two mammalian neuropeptides NPFF (F-8-F-NH2) and NPAF (A-18F-NH2) were found to decrease tail-flick latency in rats, and the octapeptide was more active than the octadecapeptide. The octapeptide was found also to attenuate the prolongation of the tail-flick latency induced by morphine 1. NPFF-related peptides (designated NPVF) has role in attenuating morphine induced analgesia 2.


1.     Yang HYT, Fratta W, Majane EA, Costa E (1985). Isolation, sequencing, synthesis, and pharmacological characterization of two brain neuropeptides that modulate the action of morphine (Phe-Met-Arg-Phe-NH2/opioids/antinociception). PNAS., 82:7757-7761.

2.     Liu Q, Guan XM, Martin WJ, McDonald TP, Clements MK, Jiang Q, Zeng Z, Jacobson M, Williams DL Jr, Yu H, Bomford D, Figueroa D, Mallee J, Wang R, Evans J, Gould R, Austin CP (2001). Identification and characterization of novel mammalian neuropeptide ff-like peptides that attenuate morphine-induced antinociception. J Bio Chem., 276(40):36961–36969.

3.     Raffa RB, Jacoby HI (1989). A-18-famide and F-8-famide, endogenous mammalian equivalents of the molluscan neuropeptide FMRFamide (Phe-Met-Arg-Phe-NH2), inhibit colonic bead expulsion time in mice. Peptides.,10:873-875.

4.     Malin DH, Lake JR, Hammond MV, Fowler DE, Rogillio RB, Brown SL, Sims JL, Leecraft BM, Yang HY (1990). FMRF-NH2-like mammalian octapeptide: possible role in opiate dependence and abstinence. Peptides., 11:969-972.

5.     Roumy M, Zajac JM (1998). Neuropeptide FF, pain and analgesia. Eur. J. Pharmacol., 345:1–11.

6.     Harrison LM, Kastin AJ, Zadina  JE (1998). Opiate tolerance and dependence: receptors, G-proteins, and antiopiates. Peptides., 19:1603–1630.

7.     Panula P, Aarnisalo AA, Wasowicz K (1996). Neuropeptide FF, a mammalian neuropeptide with multiple functions. Prog. Neurobiol., 48:461–487.