Studies were conducted on the development and loss of tolerance to morphine in the coaxially stimulated guinea-pig ileum. In ilea from guinea pigs made tolerant to morphine by the procedure of morphine-pellet implantation, the morphine-naloxone pA2 was decreased from 8.5 to 7.6, suggesting a qualitative rather than a quantitative change in the receptors. This change in the pA2 was in the opposite direction from that previously observed with analgesic receptors. Three hours after the administration of a single injection of morphine to the guinea pig, the ileum showed tolerance to morphine, which disappeared by 6 hours. With naloxone as the antagonist, the narcotic analgesics, morphine, methadone, etorphine and levorphanol, yielded higher pA2 values than the narcotic antagonist analgesics, nalorphine, pentazocine and cyclazocine, a result similar to that seen with the analgesic receptors. However, the interaction between naloxone and the narcotic antagonists in the ileum differed from that in the central nervous system when the slopes of the pAx plots were examined. Thus, although the interaction of analgesics with the ileal receptors appears to correlate with the acute effects of the drugs, caution must be exercised to use the ileal receptors as models of analgesic receptors for the study of chronic narcotic effects, i.e., tolerance and dependence.