Tolerance and cross-tolerance to the antisecretory effects of enkephalins on the guinea-pig ileal mucosa.

The antisecretory properties of opiates in the guinea-pig ileum have been shown previously to be mediated through interactions with delta-like opiate receptors present in the intestinal mucosa. The present investigation examined the development of tolerance to opioid-induced alterations in intestinal ion transport processes. Osmotic minipumps continuously delivering the prototypic delta-opioid agonist [D-Ala2,D-Leu5]enkephalin (DADLE) (5 micrograms/hr) or the potent mu-opiate agonist fentanyl (10 micrograms/hr) over a 5-day period were implanted s.c. into guinea pigs; control animals did not receive chronic drug infusions. DADLE, DADLE ethylamide and [D-Ala2,D-Met5]enkephalin dose-dependently decreased base-line transepithelial potential difference and short-circuit current in isolated segments of ileal mucosa from untreated control animals, with an order of potency of DADLE greater than [D-Ala2, D-Met5 enkephalin greater than DADLE ethylamide. In tissues from DADLE-infused animals, the antisecretory dose-effect curves of the three enkephalin analogs displayed downward shifts to the right compared to control conditions. In contrast, the potency of DADLE was significantly increased in tissues from animals chronically infused with and rendered physically dependent upon fentanyl. The administration of the opioid antagonists naloxone, diprenorphine or the selective delta-opioid antagonist M 154, 129 produced no significant changes in short-circuit current of mucosal segments from either DADLE- or fentanyl-infused animals. Chronic administration of either DADLE or fentanyl did not significantly alter the effects of nonopioids, bombesin, somatostatin or epinephrine, on ion transport; however, the efficacy but not the potency of neurotensin in increasing short-circuit current was attenuated after chronic DADLE infusion.(ABSTRACT TRUNCATED AT 250 WORDS)