COMPARATIVE ACTION OF PHE-LEU-PHE-GLN-PRO-GLN-ARG-PHE-NH2 ANALOGS ON INTESTINAL MOTILITY AND NOCICEPTION IN RATS

Central (i.c.v.) effects Of D-Tyr-D-Leu-[N-Me]-Phe-Gln-Pro-Gln-Arg-Phe -NH2 [(1DME)Y8Fa] and D-Tyr-D-LeU-D-Phe-Gln-Pro-Gln-Arg-Phe-NH2 [(3D)Y 8Fa], synthetic analogs of Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-NH2 On inte stinal myoelectric activity and nociception were studied and compared to that Of D-Ala2-Met5-enkephalinamide in rats. The duration of disrup tion of intestinal migrating myoelectric complexes, induced by p.o. ad ministration of a test meal was significantly shortened (P < .01) by ( 1 DME)Y8Fa and (3D)Y8Fa (8, 40 and 80 mug/kg) and D-Ala2-Met5-enkephal inamide (40 and 80 mug/kg). The coadministration of any two of these d rugs, at doses of nonmeasurable effect when given alone (2 mug/kg), ha s also reduced the duration (P < .01) of the postprandial intestinal m otor profile. Both separate and combined effects of drugs were antagon ized by naloxone (1 mg/kg s.c.). In contrast, in the tail-flick test, analgesia induced by D-Ala2-Met-5-enkephalinamide (40 mug/kg i.c.v.) w as blocked by (1 DME)Y8Fa, (3D)Y8Fa (8 mug/kg) and naloxone (1 mg/kg s .c.). The coadministration of (1 DME)Y8Fa and (3D)Y8Fa at doses of no proper effect when given alone (8 mug/kg) has significantly (P < .01) reduced the latency time. This effect was not blocked by naloxone (1 m g/kg s.c.). It is concluded that the Phe-Leu-Phe-Gln-Pro-Gln-Arg-Phe-N H2 analogs, (1DME)Y8Fa and (3D)Y8Fa, when given i.c.v. exert effects s imilar to opiate agonists and antagonists on intestinal myoelectrical activity and on nociception, respectively. Moreover, the synergistic t ype of effect observed after the coadministration of drugs would sugge st the involvement of multiple receptors or pathways in their mechanis m of action.