The opioid effect of α-casein fragments related to AYFYPEL and YFYPEL, which had previously shown mucin-stimulatory activity in human goblet cells, was investigated. Peptides YFYPEL and YFYPE showed opioid agonistic activity in guinea pig ileum, and in mouse vas deferens but to a lower extent. Peptides were partly hydrolysed during the assay and several of the resulting fragments lost the N-terminal Tyr residue. Docking of peptides YFYPEL (active) and YFYP (inactive) into the active site of the opioid receptor model showed remarkable differences regarding the flexibility at the third intracellular loop of the receptor and the interaction with Pro at the peptide C-terminus that forced residues Arg and Glu from the receptor to move towards the interior of the binding pocket. The study on human cells HT29-MTX has shown that YFYPEL is the minimum fragment able to stimulate MUC5AC expression.

This work has received financial support from projects AGL2015-66886-R from the Spanish Ministry of Economy and Competitiveness (MINECO), SAF2012-40075-C02-01 from the Spanish Ministry of Science and Innovation (MICINN), and FP7-SME-2012-315349 (FOFIND) financed by the European Commission (EC). S. F.-T. acknowledges MINECO for his FPI fellowship.

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