The aim of the present investigation was to determine whether chronic activation of kappa opioid receptor induces development of tolerance of kappa (specific tolerance) and to mu (cross-tolerance) agonists in the guinea pig ileum myenteric plexus-longitudinal muscle strip. trans(+/-)-3,4-dichloro-N-methyl-N-[2-(1- pyrrolidynyl)ciclohexyl]-benzeneacetamide (U-50,488H) a selective kappa agonist, morphine (prototype of a mu agonist) and DAMGO (a selective mu agonist) were chosen. Tolerance to the kappa agonist was induced by chronic administration of the kappa agonist (15 mg/kg i.p. twice a day for 4 days). The guinea pigs were killed on day 5. Tolerance to U-50,488H was observed after its chronic administration and was revealed as a rightward shift of the concentration-response curve. In addition, we observed a decrease in the maximum response and in the slope. Preparations from chronically U-50,488H-treated guinea pigs were also tolerant to the inhibitory effects of both the mu-selective agonist DAMGO and morphine. That is, there was cross-tolerance to the mu agonists. The development of tolerance to DAMGO and morphine was characterized by a rightward shift of the concentration-response curve, a decrease in maximum response and a decrease in the slope, although the degree of tolerance appeared to be less than that observed to U-50,488H. These data suggest that tolerance at the myenteric plexus level may be associated with a functional change in the myenteric neurons that is unrelated to the individual receptor system.