Blood-brain disposition and antinociceptive effects of [D- penicillamine^2,5]enkephalin in the mouse

Although intravenous administration of [D-penicillamine^2,5]- enkephalin (DPDPE) produces significant antinociception in rodents, the duration of antinociception is short (~15 min). The present study was conducted to test the hypothesis that duration of antinociception for DPDPE is determined by both systemic and regional disposition (i.e. blood-brain translocation), and that the magnitude of antinociception is related more closely to concentrations in brain tissue than in blood. Systemic disposition was examined after i.v. administration of DPDPE (10-100 mg/kg) to male CD-1 mice. The relationship between antinociception and concentration in blood and brain tissue was assessed by determining antinociception 10 min after administration of DPDPE (10-100 mg/kg); effect versus brain tissue concentration data were fit with pharmacodynamic models to recover EC₅₀ estimates. In addition the time course of antinociception, as well as blood and brain tissue concentrations were examined after an i.v. bolus dose (40 mg/kg) of DPDPE. The systemic disposition of DPDPE was nonlinear; both clearance and volume of distribution were dose-dependent. Antinociception increased proportionately with increasing concentrations of DPDPE in blood or brain tissue with an EC₅₀ of 1.42 ± 0.06 μg/g expressed as brain tissue concentration. However, the brain-to-blood concentration ratio also increased with increasing dose, suggestive of saturable translocation of DPDPE across the blood-brain barrier. Antinociception appeared rapidly (within 5 min) and dissipated within ~15 min after a 40 mg/kg i.v, dose. These results suggest that rapid elimination from blood and active efflux from brain limit the duration of action of DPDPE.