The proposed series of experiments was designed to examine the variables influencing the development of tolerance and cross tolerance to opioids with varying degrees of intrinsic efficacy at the mu receptor. In both experiments, tolerance will be induced by daily administration of the mixed-action opioid butorphanol to rats responding under an FR 20 schedule of food presentation. In experiment I, groups of rats will be administered either a low (3.0 mg/kg/day) or high (30 mg/kg/day) maintenance dose of butorphanol to examine if the magnitude of tolerance development is influenced by the maintenance dose of the toleragen. In experiment II, rats will be administered a dose of butorphanol (0.3 mg/kg/day) either before or immediately after the experimental session to determine if the temporal relationship between the time of drug administration and behavioral testing influences the degree to which tolerance and cross tolerance develop. The results of these studies will provide insight into the mechanisms by which tolerance develops to opioids and may identify some of the procedural and pharmacological variables which interact to produce differential degrees of cross tolerance among opioids
