beta-funaltrexamine and phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide

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.

Topics: Adamantane; Animals; Benzeneacetamides; Dipeptides; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Injections, Intraventricular; Male; Mice; Naltrexone; Nociception; Oligopeptides; Pyrrolidines

1. Neuropeptide FF (NPFF) has been shown to produce antinociceptive effects and enhance morphine-induced antinociception after intrathecal (i.t.) injection. In this study, the spinal effects of two NPFF analogues, -D-Tyr1,(NMe)Phe3-NPFF (1DMe) and [D-Tyr1,D-Leu2,D-Phe3]NPFF (3D), which are resistant to degradation and exhibit a high affinity for NPFF binding sites, were examined in tests of thermal and mechanical nociception. 2. 1DMe and 3D produced potent dose-dependent spinal antinociception in the tail-flick test. On a molar basis, 1DMe was 20 and 50 times more potent than 3D and morphine, respectively, and high doses of 1DMe and 3D produced a sustained antinociceptive effect without visible signs of motor impairment. 3. Spinal antinociceptive effects produced by 1DMe (0.86 nmol) or 3D (8.6 nmol) were significantly reduced by i.t. co-administration of naloxone (11 nmol) or i.t. pre-administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP, 9.25 nmol) or beta-funaltrexamine (beta-FNA, 2 nmol) or naltrindole (2.2 nmol). The doses of the mu-antagonists (CTOP and beta-FNA) or the delta-antagonist (naltrindole) used in 1DMe and 3D experiments blocked the antinociceptive effects of mu- or delta-receptor-selective agonists. 4. When administered in combination with antinociceptive doses of the mu-receptor agonist, morphine (13.2 nmol) or the delta-receptor agonist, [D-Ala2]deltorphin I (20 nmol), sub-effective dose of 1DMe or 3D (0.009 nmol) enhanced and prolonged the spinal effects of these opioid agonists. 5. The results of this study show that spinal mu- and delta-opioid receptors play a role in antinociception produced by NPFF analogues. These results also suggest a role for NPFF in modulation of nociceptive signals at the spinal level.

Topics: Amino Acid Sequence; Analgesics; Analgesics, Opioid; Animals; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Injections, Spinal; Male; Molecular Sequence Data; Morphine; Naltrexone; Narcotic Antagonists; Oligopeptides; Pain Measurement; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Somatostatin; Spinal Cord