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Previous studies have demonstrated that beta-endorphin and enkephalins are released into the systemic circulation by the pituitary and adrenal medulla, respectively. To determine whether the small intestine could be a target for circulating beta-endorphin, segments of small intestine were removed from anesthetized dogs and perfused with Krebs-bicarbonate buffer containing beta-endorphin (1 microgram/ml), while motility was recorded and venous effluent collected in 1-min fractions (23 ml). beta-Endorphin significantly (P less than .002) increased motility of intestinal segments. High-performance liquid chromatographic analysis of the venous effluent identified, among others, several alpha- and gamma-type endorphins. Several of the identified peptide fragments were then perfused through intestinal segments to determine their motility effects. alpha-Endorphin, gamma-endorphin, des-tyrosine-alpha-endorphin and des-tyrosine-gamma-endorphin, significantly increased motility at doses of 1 microgram/ml. These responses were characterized by an increase in phasic contractions of constant amplitude and frequency. To determine regional specificity and site of beta-endorphin metabolism during perfusion, we studied time course processing of beta-endorphin in mucosal and muscularis homogenates in vitro. The mucosa was much more enzymatically active than the muscularis and produced 3-fold more gamma-endorphin than alpha-endorphin, whereas the reverse was found in the muscularis. These studies demonstrate that the small intestine can metabolize beta-endorphin into a number of active fragments which increase motility and suggest a regional specificity of enzymatic processing of beta-endorphin in the dog intestine.