Abstract

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 versusbrain 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.