The experiments examined the characteristics of analgesia produced by different doses of morphine, meperidine (pethidine), fentanyl, and sufentanil after epidural and subcutaneous injection in rats. The specificity of the analgesia was also determined; other in vivo pharmacologic activities (i.e., blockade of pinna and cornea reflexes and production of skeletal muscle rigidity) were monitored as pharmacologic indices of opiate drug activity in the brain. After subcutaneous injection, the opiates produced dose-dependent analgesia, blocked the pinna and cornea reflexes, and induced muscle rigidity. After epidural injection, all four compounds produced dose-dependent analgesia and had greater potency, earlier onset, shorter duration, and greater specificity of analgesic action than was the case after subcutaneous injection. Specificity is defined here as the ratio of the ED50 dose that blocked the pinna reflex to the ED50 dose that produced analgesia. The gains in potency and specificity, but not the gains in onset time and the losses in duration of analgesia, differed considerably among the compounds that were examined. The subcutaneous-to-epidural potency ratio related in a linear manner with the lipid-to-water partition coefficient. The gain in specificity also appeared to be related to lipid solubility. The microgram X kg-1 doses at which the opiates produced analgesia in rats correlate well with the potency of these compounds in producing analgesia after epidural injection in humans. The rat epidural preparation reflected the doses, onset, and specificity, but not the duration, of analgesia produced by epidural opiates in humans.