Both N-methyl-D-aspartate (NMDA)-receptor antagonists and opiate-receptor antagonists have been shown to limit tissue damage after ischemic central nervous system injury. We compared the neuroprotective effects of the noncompetitive NMDA-receptor antagonist MK-801 and the opiate-receptor antagonist nalmefene in a model of global spinal cord ischemia and reperfusion in unanesthetized rabbits. MK-801 (1 mg/kg) or nalmefene (0.1 mg/kg) was administered intravenously 5 minutes after reperfusion. MK-801 treatment and nalmefene treatment each significantly improved the neurologic and histologic outcome compared with saline controls. Differences in these outcome measures between MK-801 treatment and nalmefene treatment did not reach statistical significance. Our results are consistent with the hypothesis that multiple factors, including endogenous opioids and excitatory amino acids, contribute to the secondary tissue injury after central nervous system ischemia. These data also provide further evidence that therapeutic interventions with opiate-receptor antagonists or NMDA antagonists may be beneficial in limiting neurologic dysfunction after ischemic brain or spinal cord injury.