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Intestinal mucus is critically involved in the protection of the mucosa. An enzymatic casein hydrolysate and [beta]-casomorphin-7, a [mu]-opioid peptide generated in the intestine during bovine casein digestion, markedly induce mucus discharge. Because shorter [mu]-opioid peptides have been described, the effects of the opioid peptides in casein, [beta]-casomorphin-7, -6, -4, -4N[H.sub.2] and -3, and of opioid neuropeptides met-enkephalin, dynorphin A and (D-Ala2,N-Me-Phe4,glycinol5)enkephalin (DAMGO) on intestinal mucus secretion were investigated. The experiments were conducted with isolated perfused rat jejunum. Mucus secretion under the influence of [beta]-casomorphins and opioid neuropeptides administered intraluminally or intra-arterially was evaluated using an ELISA for rat intestinal mucus. Luminal administration of [beta]-casomorphin-7 (1.2 x [10.sup.-4] mol/L) provoked a mucus discharge (500% of controls) that was inhibited by naloxone, a specific opiate receptor antagonist. Luminal [beta]-casomorphin-6, -4 and -4N[H.sub.2] did not modify basal mucus secretion, whereas intra-arterial administration of [beta]-casomorphin-4 (1.2 x [10.sup.-6] mol/L) induced a mucus discharge. In contrast, intra-arterial administration of the nonopioid peptide [beta]-casomorphin-3 did not release mucus. Among the opioid neuropeptides, intra-arterial infusion of Met-enkephalin or dynorphin-A did not provoke mucus secretion. In contrast, [beta]-endorphin (1.2 x [10.sup.-8] to 1.2 x [10.sup.-6] mol/L) induced a dose-dependent release of mucus (maximal response at 500% of controls). DAMGO (1.2 x [10.sup.-6] mol/L), a [mu]-receptor agonist, also evoked a potent mucus discharge. Our findings suggest that [mu]-opioid neuropeptides, as well as [beta]-casomorphins after absorption, modulate intestinal mucus discharge. Milk opioidderived peptides may thus be involved in defense against noxious agents and could have dietary and health applications. J. Nutr. 133: 3499-3503, 2003. KEY WORDS: * mucus * intestine * milk * casomorphin * opioid