A large number of opioids and nonopioids have been administered epidurally and intrathecally in the hope of providing segmental analgesia without serious adverse effects. However, neurotoxicity data are generally unavailable for many of these drugs. The present study evaluated the behavioral, motor, electroencephalographic, and histopathologic changes following intrathecal injection of large and small doses of butorphanol, sufentanil, and nalbuphine in sheep. Thirty-two sheep (20-32 kg) were anesthetized and catheters placed intrathecally after hemilaminectomy. The large doses of butorphanol, sufentanil and nalbuphine were 0.375 mg/kg (4.4-5.2 ml), 7.5 micrograms/kg (3.6-4.8 ml) and 0.75 mg/kg (1.5-2.4 ml), and the small doses were 0.075 mg/kg (0.9-1.1 ml), 1.5 micrograms/kg (0.7-0.9 ml) and 0.15 mg/kg (0.38-0.5 ml), respectively. The opioids were administered intrathecally every 6 h for 3 days and the above-mentioned parameters studied. Five sheep received intrathecal saline (1.1 or 5.2 ml) and served as controls. Histopathologic changes were evaluated by a neuropathologist blinded to the study protocol. Irrespective of dose, intrathecal injection of butorphanol was associated with severe behavioral responses such as agitation, rigidity, vocalization, and restlessness, as well as prolonged or irreversible hindlimb paralysis. Electroencephalography showed increased cortical activity or seizure activity. One sheep died because of severe respiratory depression that did not respond to naloxone. Spinal cord histologic changes consisted of suppurative meningitis and myelitis as well as neuronal changes such as spongiosis and chromatolysis. Large doses of intrathecal sufentanil were associated with similar though somewhat less severe responses. The behavioral and motor changes following the small dose of intrathecal sufentanil were of mild to moderate nature. Following intrathecal nalbuphine, the above-mentioned changes were similar to those seen in control animals. We conclude that butorphanol in doses of 0.075 and 0.375 mg/kg intrathecally and sufentanil 7.5 micrograms/kg intrathecally are neurotoxic in sheep.