When injected directly into the tail, U50,488H is a potent analgesic in the tailflick assay (ED50 3.1 micrograms). The analgesic activity is lost if the radiant heat is focused 1 cm away from the site of injection. The kappa 1-opioid receptor antagonist nor-binaltorphimine given systemically reverses the local analgesic response of U50,488H, but the antagonist is 100-fold more potent when injected directly into the tail. Intrathecal antisense treatment with a probe targeting the mRNA encoding the kappa 1-opioid receptor blocks the local analgesic actions of U50,488H in the tail, suggesting that U50,488H is acting on dorsal ganglia neurons.