RESUMEN
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.
Asunto(s)
Hormonas de Invertebrados/farmacología , Neuropéptidos/farmacología , Péptidos Opioides/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , FMRFamida , Hormonas de Invertebrados/química , Hormonas de Invertebrados/genética , Leucil Aminopeptidasa/metabolismo , Masculino , Metionina/análogos & derivados , Metionina/química , Datos de Secuencia Molecular , Dependencia de Morfina/metabolismo , Neuropéptidos/química , Neuropéptidos/genética , Oligopéptidos/química , Oligopéptidos/genética , Fenilalanina/análogos & derivados , Fenilalanina/química , Ratas , Ratas Sprague-Dawley , Receptores de Neuropéptido/metabolismo , EstereoisomerismoRESUMEN
Neuropeptide FF (NPFF) has been shown to exert various antiopiate actions, including precipitation of opiate abstinence syndrome by third ventricle injection in morphine dependent rats. In the present study, dansyl-Pro-Gln-Arg-Phe-amide, a lipophilic analog of NPFF, was injected into morphine dependent rats and appropriate sham controls at a dose of 9 mg/kg s.c. Comparison groups were injected with ethanol/water vehicle alone. The NPFF analog precipitated a vigorous opiate abstinence syndrome in morphine dependent rats, but not in sham controls.
Asunto(s)
Morfina/efectos adversos , Neuropéptidos/farmacología , Oligopéptidos/farmacología , Síndrome de Abstinencia a Sustancias , Secuencia de Aminoácidos , Animales , Inyecciones Subcutáneas , Masculino , Datos de Secuencia Molecular , Morfina/antagonistas & inhibidores , Dependencia de Morfina , Ratas , Ratas Sprague-DawleyRESUMEN
Previous studies suggest that neuropeptide FF (NPFF) plays a role in opiate dependence and subsequent abstinence syndrome. Endogenous NPFF also appears to play a role in opiate tolerance since third ventricle injection of IgG from NPFF antiserum selectively restores morphine sensitivity in morphine-tolerant rats. The NPFF analog, desamino YFLFQPQRamide (daY8Ra) has previously antagonized behavioral effects of NPFF and has attenuated morphine dependence. The present study assessed whether daY8Ra could similarly attenuate morphine tolerance. Third ventricle (i.c.v.) injection of daY8Ra restored the analgesic response to i.c.v. morphine in morphine-tolerant rats (radiant heat tail flick test). Saline injection failed to produce this effect. In opiate-naive rats, however, the same treatment with daY8Ra did not affect the analgesic response to i.c.v. morphine. Thus, daY8Ra appears to selectively restore morphine sensitivity in opiate-tolerant animals. These results further support the hypothesis that endogenous NPFF contributes to opiate tolerance.