The unidirectional non-cross tolerance (UNCT) phenomenon describes the situation in which morphine pellet implanted animals (with pellet in place) manifest a large degree of tolerance to s.c. morphine but no tolerance to s.c. heroin or etorphine. Because these mice show no tolerance to morphine given intracerebroventricularly, we postulated that the differential development of tolerance to s.c. morphine resides in a "dispositional blood brain barrier" type of mechanism which is circumvented by giving the morphine intracerebroventricularly. After removal of the morphine pellet, the mice now show cross-tolerance to heroin and etorphine, a state we labeled withdrawal tolerance. Specificity of the UNCT phenomenon will be investigated to see whether the spinal centers mediating the same tail flick analgesic response act in the same way as the supraspinal centers. Does a "blood brain barrier" type of mechanism of tolerance apply? Also, the effect of tolerance on the interaction that normally occurs between supraspinal and spinal centers will be studied by simultaneous intracerebroventricular and intrathecal ED50 determinations. The longitudinal changes in the withdrawal tolerance will also be similarly studied. A mechanism more proximal to the receptors than the blood brain barrier may be localization of morphine in cerebroside sulfate. Because the differential tolerance to s.c. morphine seen in the UNCT situation depends on the hydrophilicity of morphine, a much more hydrophiliccompound, morphine-6-ethereal sulfate will be included. This compound is 45 times more potent intracerebroventricularly than morphine. Possibility of its formation in the brain will be investigated. Studies on the persisting morphine pool also relate to localization and tolerance.