Experiments were designed to test for short-term tolerance to morphine and ethyl-ketocyclazocine (EKC), mu and kappa agonists, respectively, and cross-tolerance between the two drugs. Mice were primed with one of the drugs, using doses that did not affect the tail-flick response when tested at a time 1 or 3 hours later, when the same or alternate test drug was administered. All animals were injected with the priming drug IP. In one series of experiments, the test drugs were given SC, and in the other, the test drugs were injected ICV under brief halothane anesthesia. Priming with morphine (30 or 100 mg/kg) significantly raised the ED50 for ICV morphine. Priming with EKC (2 or 6 mg/kg) similarly elevated the ED50's for SC and ICV EKC. Symmetrical cross--tolerance was produced in experiments where the test drugs were administered SC when tested at 3 hrs. The effects of priming with EKC on morphine analgesia was evident when the interval between priming and test drugs was 1 hour. When the test drugs were given ICV, cross-tolerance was also symmetrical: priming with EKC significantly raised the ED50 for morphine and priming with morphine raised the ED50 for EKC when tested at 3 hrs. These data suggest that both agonists act on a common site to produce analgesia as similar pA2 values for naloxone antagonism were determined. The occurrence of short-term tolerance and cross-tolerance to the opiates was unaltered by chronic pretreatment with diazepam, phenobarbital, or amphetamine.