The occurrence of unidirectional noncross-tolerance to heroin and etorphine induced antinociception in morphine tolerant mice prompted this study to determine whether this phenomenon occurs for opiate induced inhibition of intestinal transit. Tolerance to the intestinal inhibitory effect (charcoal meal test) of s.c. morphine, etorphine and heroin was reflected by an increase in the ED50 value and in most cases, a flattening of the dose response curve in morphine and etorphine pelleted mice (tested with pellet in place). A similar response was noted following intracerebroventricular administration of these agents in morphine pelleted mice. More tolerance developed to the relatively hydrophilic compound morphine than to the lipophilic compounds etorphine and heroin. Factors related to hydrophilicity and lipophilicity may be involved in the development of tolerance to opiates in the intestine although unidirectional non cross-tolerance did not occur.