Review
Neuropeptide FF, pain and analgesia

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Abstract

Neuropeptide FF (Phe–Leu–Phe–Gln–Pro–Gln–Arg–Phe–NH2) and the octadecapeptide neuropeptide AF (Ala–Gly–Glu–Gly–Leu–Ser–Ser–Pro–Phe–Trp–Ser–Leu–Ala–Ala–Pro–Gln–Arg–Phe–NH2) were isolated from bovine brain, and were initially characterized as anti-opioid peptides. They can oppose the acute effects of opioids and an increase in their brain concentrations may be responsible for the development of tolerance and dependence to opioids. Numerous experiments suggest a possible neuromodulatory role for neuropeptide FF. A precursor protein has been identified, in particular in human brain. Neuropeptide FF immunoreactive neurons are present only in the medial hypothalamus, and the nucleus of the solitary tract, and in the spinal cord in the superficial layers of the dorsal horn and areas around the central canal. Depolarization induces a Ca2+-dependent release of neuropeptide FF immunoreactivity from the spinal cord. Neuropeptide FF acts through stimulation of its own receptors and high densities of specific binding sites are found in regions related either to sensory input and visceral functions or to the processing of nociceptive messages. In both isolated dorsal root ganglion neurons and CA1 pyramidal neurons of the hippocampus, neuropeptide FF has little effect of its own but reverses the effects of μ-opioid receptor agonists. In agreement with the hypothesized anti-opioid role of neuropeptide FF, supraspinal injection lowers the nociceptive threshold and reverses morphine-induced analgesia in rats. Furthermore, immunoneutralization of neuropeptide FF increases endogenous and exogenous opioid-induced analgesia. Similarly, microinfusion of neuropeptide FF or neuropeptide FF analogs into the nucleus raphe dorsalis, the parafascicular nucleus, or the ventral tegmental area has no effect on the nociceptive threshold but inhibits the analgesia induced by co-injected morphine. Furthermore, infusion of neuropeptide FF into the parafascicular nucleus or the nucleus raphe dorsalis reverses the analgesic effect of morphine infused into the nucleus raphe dorsalis or the parafascicular nucleus, respectively, demonstrating remote interactions between neuropeptide FF and opioid systems. By contrast, intrathecal administration of neuropeptide FF analogs induces a long lasting, opioid-dependent analgesia and potentiates the analgesic effect of morphine. Analgesic effects of neuropeptide FF after supraspinal injection could also be observed, for example during nighttime. In young mice, (1DMe)Y8Famide (d.Tyr–Leu–(NMe)Phe–Gln–Pro–Gln–Arg–Phe–NH2), a neuropeptide FF analog, increases δ-opioid receptor-mediated analgesia. These findings indicate that neuropeptide FF constitutes a neuromodulatory neuronal system interacting with opioid systems, and should be taken into account as a participant of the homeostatic process controlling the transmission of nociceptive information.

Introduction

Neuropeptide FF (NPFF, Phe–Leu–Phe–Gln–Pro–Gln–Arg–Phe–NH2) and the octadecapeptide neuropeptide AF (Ala–Gly–Glu–Gly–Leu–Ser–Ser–Pro–Phe–Trp–Ser–Leu–Ala–Ala–Pro–Gln–Arg–Phe–NH2) were isolated from bovine brain (Yang et al., 1985) using an antiserum directed against the molluscan peptide FMRFamide (Phe–Met–Arg–Phe–NH2; Price and Greenberg, 1977). Neuropeptide FF has been variously referred to as mammalian FMRFamide-like peptide, F8Famide or morphine modulating neuropeptide since neuropeptide FF like FMRFamide decreases the nociceptive threshold of rats (Yang et al., 1985). Invertebrate FMRFamide and small cardioactive peptides with an N-terminal Arg–Met-amide amino acid sequence exist in almost all molluscan species where they might function as neuromodulators or neurotransmitters. The amino acid sequence similarity between FMRFamide and the opioid peptide [Met5]enkephalin–Arg6–Phe7–amide pointed to possible structural and functional similarities in the two peptide families (Greenberg et al., 1983).

Neuropeptide FF together with cholecystokinin (CCK8-S, Asp–Tyr(SO3H)–Met–Gly–Trp–Met–Asp–Phe–NH2) or Tyr-MIF-1-like peptides (Tyr–Pro–Leu–Gly–NH2) are termed anti-opioid substances indicating that the morphine-induced changes in neuronal responses involve various non-opioid neurotransmitter networks that participate in an homeostatic system which acts to damp the effects of opioids. Accordingly, in addition to pain inhibiting pathways, there are anti-analgesic neuronal peptides which act by blocking pain inhibition in the central nervous system. The triggering of these systems readily explains the development of tolerance and dependence induced by chronic administration of opioids.

An anti-opioid model of tolerance and dependence (Rothman, 1992) postulates the existence of endogenous compounds that are able to reduce some of the acute (in particular antinociceptive) opioid effects, and permanently mask the effects of exogenous and endogenous opioids. Accordingly, chronic treatment with morphine should increase the release of anti-opioid peptides which, by stimulating specific receptors and specific networks, attenuate the pharmacological effects of morphine. As more opioid is given, more anti-opioid is released inducing tolerance to opioid effects. Following cessation of opioid administration, residual excess of anti-opioid is partly responsible for the withdrawal syndrome.

This model implies that anti-opioid peptides such as neuropeptide FF should be considered as tonic modulators of opioid functions. They therefore present an important target for new pharmacological agents able to modulate endogenous opioid function and amplify analgesic opioid effects. Agonists of the anti-opioid system are anticipated to block the analgesia produced by administration of opioids, whereas antagonists or antisera against anti-opioid peptides would potentiate analgesia.

Our knowledge of the neuropeptide FF system is now sufficiently advanced to describe (in broad terms) the role of neuropeptide FF peptides in the central control of opioid function.

Section snippets

Neuropeptide FF as a neurotransmitter/neuromodulator

Neuropeptide FF and neuropeptide AF were first isolated from bovine brain, and neuropeptide FF-like immunoreactivity was later demonstrated in the central nervous system of several mammals including humans (Panula et al., 1987; Majane et al., 1988; Kivipelto et al., 1989). Currently known peptide sequences of the neuropeptide FF family in various species are summarized in Table 1. A gene encoding both neuropeptide FF and neuropeptide AF has been reported in bovine, rat, mouse and human (Vilim

Anti-opioid effects of neuropeptide FF

The location of neuropeptide FF receptors in networks involved in pain modulation correlates well with the results of pharmacological experiments. Several studies have evidenced a role for neuropeptide FF in nociception and in the control of opioid functions and according to the anti-opioid model, neuropeptide FF produces hyperalgesia and inhibits opioid-induced analgesia.

Pro-opioid effects of neuropeptide FF

In contrast to pharmacological effects observed in rats and mice following supraspinal injection, other evidence has accumulated indicating that neuropeptide FF may display opioid-like effects dependent upon the animal model, injection route and pharmacological tests used. Thus, i.t. injections of neuropeptide FF or its analog (1DMe)Y8Famide produce a long-lasting analgesia in rats (Gouardères et al., 1993, Gouardères et al., 1996a). This analgesia is, however, opioid systems-dependent, since

Anti-opioid model and analgesia

The apparent contradiction between anti-opioid and analgesic effects of neuropeptide FF relates not only to spinal and supraspinal injection sites since, during the dark phase, neuropeptide FF can induce analgesia after i.c.v. injection (Oberling et al., 1993).

After i.c.v. injection in rats, the hyperesthesic effect of neuropeptide FF was followed, during nighttime, by a clear analgesic effect. The magnitude of the analgesic effect was observed to be dependent upon that of preceding

Conclusion

Neuropeptide FF constitutes a neuromodulatory neuronal system that is involved in the control of the transmission of nociceptive information. More precisely, neuropeptide FF appears to be a modulator of opioid antinociceptive function.

Neuropeptide FF has clear antiopioid effects, mostly at the supraspinal level. These have been demonstrated after i.c.v. injection, after microinfusion into particular brain nuclei and even at the level of the single isolated neuron. By reason of its antiopioid

Acknowledgements

We are particularly indebted to Dr J.C. Meunier for his critical comments and to Dr. C. Topham for correcting English style. Our research is supported by the Centre National de la Recherche Scientifique, the Ministère de l'Education Nationale, de l'Enseignement Superieur et de la Recherche (97H004).

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