Doses of sufentanil (i.e., 0.01, 0.04, 0.16, 0.63, 2.5, 10, and 40 μg/rat) were injected either into the lumbar epidural space or intravenously in rats weighing ± 250 g, andin vivopharmacologic activities (i.e., prolongation of latency to tail withdrawal in response to noxious heat, blockade of cornea and pinna reflexes, increase of skeletal muscle tone),ex vivoμ-opiate receptor binding (i.e., displacement of specific3H-sufentanil binding in thalamus, striatum, hippocampus, cortex, mamillary body-medulla oblongata segment, medulla oblongata, and in cervical, thoracic, and lumbar spinal cord), and drug concentrations in plasma, brain, cortex, and cerebellum, were determined. An ED50dose of intravenous sufentanil of 0.075 μg/rat produced analgesia. CNS-mediatedin vivoside effects (i.e., blockade of pinna and cornea reflexes, muscle rigidity) were apparent at 6–28 times higher doses. Epidural sufentanil also produced analgesia at an ED50dose of 0.08 μg/rat, but CNS-mediated side effects occurred only at 35 to 76 times higher doses. This greaterin vivoselectivity of epidural sufentanil in producing analgesia was consistent withex vivobinding data that showed that in most areas of brain, but not in spinal cord, more μ-opiate binding occurs with intravenous than with epidural sufentanil. The two routes nonetheless differed by no more than a factor of approximately two in producing detectable levels of sufentanil both in plasma and in brain tissue. Analgesia produced by epidural sufentanil in rats may originate at least in part at μ-opiate receptor sites in the spinal cord; but the minute amounts of sufentanil that may reach the brain after epidural injection of low doses of the drug may perhaps amplify the spinal action.