Conformationally constrained cyclic enkephalin analogs which possess a high selectivity for the delta opioid receptor were used to determine the relative contribution of mu and delta receptors to brain-mediated changes in small intestinal propulsion and increases in hot-plate response time. Receptor preferences were determined by comparing the relative potencies of several opioid agonists in suppressing the electrically evoked contractions of the guinea-pig ileum and mouse vas deferens preparations. The ratio of IC50 values obtained in the guinea-pig ileum and the mouse vas deferens was used as an index of delta receptor selectivity. Effects on intestinal transit were determined in rats in which a silastic cannula had been implanted in the proximal duodenum and a polyethylene cannula in the right lateral cerebral ventricle (i.c.v.). Movement of a radioactive marker along the length of the small intestine after instillation into the duodenum was used to evaluate drug-induced changes in intestinal transit. The analgesic effects of i.c.v. administered opioids were determined in a second group of rats in which i.c.v. cannulas alone had been implanted. After i.c.v. administration of the agonist, the rats were placed on a 55°C hot plate and the latency to rear paw-lick was timed. Compounds which showed a preference for the mu receptor ([D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin and morphine/normorphine) were the most potent agonists at producing thermal analgesia and inhibition of small intestinal transit, whereas nonselective compounds (β-endorphin and [D-Ala2, Met5]enkephalinamide) were slightly less potent in these assays. As delta receptor selectivity increased ([D-Pen2, D-Pen5]enkephalin > [D-Pen2, L-Pen5]enkephalin > [D-Pen2, L-Cys5]enkephalin > [D-Ala2, D-Leu5]enkephalin), potency at inhibiting intestinal transit decreased markedly, whereas potency for producing thermal analgesia decreased only slightly. The analgesic effects of [D-Ala2, N-methyl-Phe4, Gly5-ol]enkephalin, [D-Pen2, L-Cys5]enkephalin, [D-Pen2, L-Pen5]enkephalin and [D-Pen2, D-Pen5]enkephalin were all antagonized by naloxone pretreatment (2.0 mg/kg). U-50,488H, a kappa selective compound, did not affect intestinal transit at any dose tested and increased hot-plate latencies only at the highest dose (125 μg). These data indicate that mu receptors exclusively mediate the intestinal motility effects of i.c.v. administered opioids, whereas both mu and delta receptors can mediate the analgesic effects in rats.
|Original language||English (US)|
|Number of pages||8|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - 1984|
ASJC Scopus subject areas
- Molecular Medicine