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Neuropeptide FF (NPFF) has certain antiopiate actions and may play a role in opiate tolerance and dependence. Third ventricle injection of 10 micrograms NPFF induces a quasimorphine abstinence syndrome in opiate-naive rats. Nitric oxide synthesis may also contribute to opiate tolerance and dependence. The present study tests the hypothesis that NPFF acts through stimulation of nitric oxide synthase (NOS). Third ventricular injection of 10 micrograms NPFF precipitated an average of 46 abstinence-like signs during a 20-min observation. Pretreatment (30 min earlier) with 7.5 or 15 mg/kg s.c. of the NOS inhibitor nitro-L-arginine (L-NNA) resulted in a significant and dose-dependent alleviation of NPFF-induced abstinence-like signs. The anti-NPFF activity of 15 mg/kg L-NNA was blocked by 750 mg/kg L-arginine, but not by the same amount of D-arginine, indicating that L-NNA attenuates NPFF activity through a stereospecific inhibition of NOS.

FMRFamide is a molluscan peptide that has shown antiopiate activity in a number of mammalian test systems. Peptidomimetics of FMRFamide substituted with conformationally constrained stereoisomers of Z-2,3-methanomethionine or E-2,3-methanomethionine precipitated abstinence syndrome far more potently than FMRFamide itself. The current study determined the effect on antiopiate potency of an additional rigid substitution. A peptidomimetic containing a stereoisomer of E-2,3-methanomethionine was compared with a peptidomimetic additionally substituted at the C-terminal with E-2,3-methanophenylalanine. Morphine abstinence signs were observed after varying doses (0.125-25.0 micrograms) of these two peptidomimetics were injected into the third ventricle of morphine-dependent rats. The peptidomimetic containing both rigid substitutions was far more potent than the peptidomimetic of FMRFamide containing methanomethionine alone. The increased potency appears to be related to enzyme resistance rather than receptor affinity.

FMRFamide is a molluscan peptide that has shown antiopiate activity in a number of mammalian test systems. The current study determined the antiopiate potency of FMRFamide and two conformationally constrained peptidomimetics of FMRFamide containing stereoisomers of (E)-2,3-methanomethionine. Morphine abstinence signs were observed after varying doses (0.25-25.0 microgram) of these substances were injected into the third ventricle of morphine-dependent rats. Both peptidomimetics were far more potent than FMRFamide itself. In addition, although both peptidomimetics bound with lower affinity than FMRFamide to rat spinal cord receptors for NPFF (the mammalian FMRFamide-like peptide), they were far more resistant than FMRFamide to enzymatic degradation by leucine aminopeptidase.

FMRFa is a molluscan peptide that has shown antiopiate activity in a number of mammalian test systems. The current study determined the antiopiate potency of FMRFa and two conformationally constrained peptidomimetics of FMRFa containing stereoisomers of Z-2,3-methanomethionine. Morphine abstinence signs were observed after varying doses (0.25-25.0 micrograms) of these substances were injected into the third ventricle of morphine-dependent rats. Although both peptidomimetics were far more potent than FMRFa itself, they bound with lower affinity than FMRFa to rat spinal cord receptors for the mammalian FMRFa-like peptide, NPFF.

The octapeptide FLFQPQRFamide (neuropeptide FF or F8Fa) may play a role in opiate dependence and subsequent abstinence syndrome. Previously, NPFF precipitated opiate abstinence syndrome, while IgG from NPFF antiserum attenuated subsequent naloxone-precipitated abstinence signs in dependent rats. The peptide desamino YFLFQPQRamide (daY8Ra) was synthesized as a possible NPFF antagonist. At a dose of 600 ng ICV, daY8Ra significantly attenuated (p less than 0.001) the number of abstinence-like signs subsequently induced by 10 micrograms NPFF ICV, suggesting that daY8Ra does have antagonist activity against NPFF. Pretreatment of morphine-dependent rats with the same dose of daY8Ra also significantly attenuated (p less than 0.001) the abstinence signs subsequently precipitated by 10 micrograms naloxone ICV. Pretreatment with 600 ng of NPFF itself, or of NPFF modified at the N-terminal only (daY9Fa), failed to attenuate subsequent naloxone-precipitated abstinence, suggesting that the C-terminal modification is critical for NPFF antagonist activity. It should be noted, however, that higher doses of daY8Ra (2 micrograms or more) can precipitate some abstinence signs in a manner similar to NPFF.

Yang et al. have isolated from bovine brain an octapeptide, FLFQPQRF-NH2 (F-8-F-NH2), with certain antiopiate properties. Malin et al. previously found that ICV injection of this peptide could precipitate an opiate abstinence syndrome in dependent rats. RIA revealed significantly higher levels of F-8-F-NH2 immunoreactivity in CSF withdrawn from the cisterna magna of morphine-dependent rats as opposed to CSF withdrawn from sham-implanted controls. ICV infusion of IgG from antiserum against F-8-F-NH2 significantly reduced the number of abstinence signs subsequently precipitated by naloxone in morphine-dependent rats.

Yang et al. (14) have isolated from mammalian brain an octapeptide FLFQPQRF-NH2 (F-8-F-NH2) with certain antiopiate properties. Third ventricular injection of 2 micrograms of this peptide together with the aminopeptidase inhibitor bestatin precipitated an opiate-withdrawal syndrome in morphine-dependent but not in nondependent rats. Third ventricular injection in nondependent rats of 15 micrograms of the peptide together with bestatin induced a morphine-withdrawal-like behavioral syndrome. This syndrome was not produced by injection of bestatin or saline vehicle alone and was preventable by injection of 3.5 mg/kg morphine sulphate SC.