κ-Opioid antagonist improves cellular bioenergetics and recovery after traumatic brain injury

Treatment with opioid receptor antagonists improves outcome after experimental brain trauma, although the mechanisms underlying the protective actions of these compounds remain speculative. We have proposed that endogenous opioids contribute to the pathophysiology of traumatic brain injury through actions at κ-opioid receptors, possibly by affecting cellular bioenergetic state. In the present study, the effects of the κ-selective opioid-receptor antagonist nor-binaltorphimine (nor-BNI) were examined after fluid percussion brain injury in rats. Metabolic changes were evaluated by ³¹P magnetic resonance spectroscopy; the same animals were subsequently followed over 2 wk to evaluate neurological recovery. Nor-BNI, administered intravenously as a 10 or 20 mg/kg bolus at 30 min after injury, significantly improved neurological outcome at 2 wk posttrauma compared with controls. Animals treated with nor-BNI showed significantly greater recovery of intracellular free magnesium concentrations and cytosolic phosphorylation potentials during the first 4 h after injury compared with saline-treated controls. The improvement in cytosolic phosphorylation potential was significantly correlated to neurological outcome. These data support the hypothesis that κ-opioid receptors mediate pathophysiological changes after traumatic brain injury and that the beneficial effects of opioid-receptor antagonists may result from improvement of posttraumatic cellular bioenergetics.