Abstract
Neuropeptide FF (NPFF) is known to be an endogenous opioid-modulating peptide. Nevertheless, very few researches focused on the interaction between NPFF and endogenous opioid peptides. In the present study, we have investigated the effects of NPFF system on the supraspinal antinociceptive effects induced by the endogenous µ-opioid receptor agonists, endomorphin-1 (EM-1) and endomorphin-2 (EM-2). In the mouse tail-flick assay, intracerebroventricular injection of EM-1 induced antinociception via µ-opioid receptor while the antinociception of intracerebroventricular injected EM-2 was mediated by both µ- and κ-opioid receptors. In addition, central administration of NPFF significantly reduced EM-1-induced central antinociception, but enhanced EM-2-induced central antinociception. The results using the selective NPFF1 and NPFF2 receptor agonists indicated that the EM-1-modulating action of NPFF was mainly mediated by NPFF2 receptor, while NPFF potentiated EM-2-induecd antinociception via both NPFF1 and NPFF2 receptors. To further investigate the roles of µ- and κ-opioid systems in the opposite effects of NPFF on central antinociception of endomprphins, the µ- and κ-opioid receptors selective agonists DAMGO and U69593, respectively, were used. Our results showed that NPFF could reduce the central antinociception of DAMGO via NPFF2 receptor and enhance the central antinociception of U69593 via both NPFF1 and NPFF2 receptors. Taken together, our data demonstrate that NPFF exerts opposite effects on central antinociception of endomorphins and provide the first evidence that NPFF potentiate antinociception of EM-2, which might result from the interaction between NPFF and κ-opioid systems.
Highlights
In 1985, Neuropeptide FF (NPFF) was isolated from bovine medulla oblongata and characterized as an anti-opioid peptide [1]
The endogenous m-opioid receptor ligands endomorphins, especially EM-2 were reported to induce antinociceptive effect mediated by the different mechanisms [32,33,34,39,40]
The central antinociceptive effect of EM-1 was blocked by pretreatment with m-opioid receptor antagonist b-FNA, but not by k-opioid receptor antagonist nor-BNI or d-opioid receptor antagonist naltrindole
Summary
In 1985, NPFF was isolated from bovine medulla oblongata and characterized as an anti-opioid peptide [1]. NPFF and related peptides were found to exhibit anti-opioid effects via NPFF1 and NPFF2 receptors in isolated neurons and recombinant cellular models [15,16,17,18,19,20]. The previous reports suggested that supraspinal administration of NPFF exerted anti-opioid properties in feeding behaviour, locomotor activity and rewarding effect [11,14]. NPFF produced a bimodal effect on pain perception: NPFF receptors agonists exerted anti- or pro-opioid effects depending on their route of administration and the level of opioid-induced analgesia [13,23]. Intrathecal administration of NPFF exerted a pro-opioid role and induced an opioid-like analgesia or potentiated morphine analgesia [26,27]
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