Treatment of CNS trauma with the opiate antagonist naloxone improves outcome, though the mechanisms of action remain speculative. Nalmefene is another opiate-receptor antagonist, but it has substantially greater potency and duration of action than naloxone. It also has increased activity at kappa opiate receptors and has recently been shown to limit histological changes and neurological dysfunction after traumatic spinal cord injury. The present study examined the effects of treatment with nalmefene on outcome after fluid-percussion-induced traumatic brain injury in rats, using magnetic resonance spectroscopy to monitor acute metabolic changes and behavioral tests to determine chronic neurological recovery. Single-dose treatment with nalmefene (100 micrograms/kg, i.v.) at 30 min after trauma significantly improved (p less than 0.05) neurological outcome (up to 4 weeks) as compared to saline-treated controls. Early changes in intracellular free-magnesium concentration, adenosine diphosphate concentration, and cytosolic phosphorylation potential were all significantly improved by nalmefene treatment, reflecting improved bioenergetic state. We suggest that the ability of nalmefene to improve cellular bioenergetics after trauma may in part account for the neuroprotective effects of this and related compounds.