A new technique of epidural catheterization in rats is described. The pharmacologic characterizations of the model were established after epidural injection of bupivacaine, morphine, fentanyl, lofentanil, and D-Ala2-D-Leu5-enkephalin (DADL) on hot plate (HP) and tail flick (TF). In addition, rostral spread, motor function, behavior, and reproducibility of the effects over time were assessed. The time-response curves showed an almost immediate onset of action for bupivacaine, fentanyl, and lofentanil and a delayed onset for morphine and DADL. Morphine and lofentanil displayed a significantly longer duration of action than bupivacaine, fentanyl, and DADL. The dose-response curves were monotonic and the slopes were log-linear. Based on the ED50values, the following rank order of potency was obtained 1 day after catheterization for both HP and TF: lofentanil ≫ fentanyl > morphine ≫ DADL > bupivacaine. Intraperitoneal (IP) administration of naloxone antagonizes the agonist effects of epidural morphine, fentanyl, and lofentanil. To assess the role in analgesia played by epidural vascular uptake after epidural administration of morphine, fentanyl, and lofentanil, the lowest maximally effective epidural dose of these agents was given intravenously. After iv fentanyl and lofentanil, the analgesic and behavioral effects were not different from the values obtained after epidural administration. By contrast, the effects were negligible after iv morphine when compared with the epidural route. Epidural vascular uptake is thought to be low for morphine and high for fentanyl and lofentanil. The reproducibility of the analgesic and behavioral effects over time was assessed by epidurally injecting the lowest maximally effective dose of bupivacaine, morphine, fentanyl, and lofentanil 1 day and 10 days after catheterization. After 10 days, a significant reduction of analgesic and behavioral effects was noted and was thought to be due to a complete fibrotic sheath surrounding the epidural catheter.