After 10-minute incubation of [H-3]-tyrosine methionine(5)-enkephalin (MET) with 100,000 X g supernatant from select brain regions of patients with chronic schizophrenia (n = 3), essentially all of the labeled tyrosine was recovered as the free amino acid. Initial velocity and half-life of MET degradation obtained from different brain areas (limbic system, thalamus, basal ganglia, cerebellum, and cortex) of individual brains or from equivalent sections from different brains were scattered and considerable spread out (brains A, B, and C: 21.7-60.2 and 2.1-14.3, 25.6-88.7 and 1.6-14.1, 24.5-56.1 and 2.6-14.3 pg MET/mg brain tissue/min and min, respectively; brains A-C range, 21.7-88.7 pg MET/mg brain tissue/min and 1.6-14.3 min, respectively). These results failed to identify consistent differences in peptide degradation kinetics between the various brains areas studied from the same individual or from equivalent section from different subjects. MET metabolic rate was pH and temperature-dependent (optimum 7.4 degrees C and 37 degrees C), reduced by the aminopeptidase inhibitors puromycin, bacitracin, and bestatin, and to a lesser extent by thioridazine. However, peptide metabolism was not significantly affected by differences in tissue storage time or repeated freezing and thawing; by preincubation with N-carboxymethyl phenyl leucine, captopril, or thiorphan (dipeptidyl peptidase[s] or peptidyl dipeptidase[s] inhibitors, respectively); or by the many different drugs used by the patients with chronic schizophrenia. Our findings, although of a preliminary nature and generally similar to those recently reported for comparable studies on nonneuropsychiatric patients, provide a much needed understanding of the mechanisms regulating brain MET metabolism. Whether these results may contribute to the rational design of pharmacologic strategies for the treatment of pathologies associated with alterations in the enkephalinergic system needs further research.