Nalmefene is an opiate receptor antagonist, derived from naltrexone, that has a significantly longer plasma half-life than naloxone after i.v. administration and that may have enhanced activity at kappa opiate receptors. Because of the demonstrated beneficial effects of other opiate-receptor antagonists in spinal cord injury (SCI) and the postulated role of kappa opiate receptors in such injury, nalmefene treatment was evaluated in a well-characterized model of traumatic SCI in rats. In a randomized blinded study, nalmefene treatment, given as a single i.v. bolus injection at 60 min posttrauma, significantly improved neurological recovery and reduced tissue damage. Beneficial actions were dose-related. The optimal dose was 0.1 mg/kg, with diminished effects at both higher and lower doses; this is approximately 1% of the optimal naloxone dose in SCI as shown from other studies. Nalmefene, given i.t. at doses that were ineffective systemically, significantly improved neurological recovery after spinal trauma. These findings are consistent with the hypothesis that endogenous opioids, acting at opiate receptors within the spinal cord, mediate certain secondary pathophysiological changes that contribute to irreversible tissue injury. If current clinical trials with naloxone in SCI prove successful, the profile of nalmefene would make it a candidate for use in future clinical studies.