Effect of D-alanine methionine enkephalin amide on ion transport in rabbit ileum

The presence of enkephalins in the intestine and the use of opiates to treat diarrheal diseases suggests that enkephalins may affect intestinal ion transport. Using isolated rabbit ileal mucosa, we found that leucine enkephalin, methionine enkephalin, and D Ala2-methionine enkephalin amide (D Ala2-Met E) decreased the short circuit current (Isc) and potential difference although the effect of D Ala2-Met E was more pronounced and prolonged. D Ala2-Met E increased net sodium (+1.27 +/- 0.5 mu eq/cm2h), and chloride absorption (+2.33 +/- 0.4), and increased tissue conductance by 37%. Although the effect of enkaphalin on ion transport is opposite that of cyclic AMP, D-Ala2-Met had no effect on basal or vasoactive intestinal polypeptide-stimulated cyclic AMP levels. The effect of D-Ala2-Met E on Isc was blocked by naloxone, suggesting the involvement of specific opiate receptors. Tetrodotoxin completely blocked the decrease in Isc induced by D-Ala2-Met E but not by epinephrine, inferring that enkephalins are preganglionic neurotransmitters. The effect of D-Ala2-Met E on Isc was not blocked by phentolamine, haloperidol, or pretreatment of animals with 6-hydroxydopamine, suggesting that enkephalin does not affect the Isc by stimulating the release of alpha-adrenergic or dopaminergic agonists. D-Ala2-Met E also decreased the Isc in the presence of carbachol and bethanechol, indicating that enkephalin does not inhibit the release of acetylcholine. Further, up to 10 mu M atropine had no effect on the Isc. These studies demonstrate that enkephalins stimulate intestinal ion transport and may do so by stimulating (or inhibiting) the release of a nonadrenergic, noncholinergic neurotransmitter.