Enhanced antinociception of the model opioid peptide [D- Penicillamine^2,5] enkephalin by P-glycoprotein modulation

Purpose. This study was conducted to examine the influence of P- glycoprotein (P-gp) modulation on the pharmacodynamics of the model opioid peptide DPDPE. Methods. Mice (n = 5-7/group) were pretreated with a single oral dose of the P-gp inhibitor GF120918 (25 or 250 mg/kg) or vehicle. ³H- DPDPE (10 mg/kg) or saline was administered 2.5 hr after pretreatment. Antinociception was determined, and blood and brain tissue were obtained, 10 min after DPDPE administration. Results. A significant difference (p < 0.001) in DPDPE-associated antinociception was observed among mice pretreated with a 25-(83 ± 16% MPR) or 250- (95 ± 5% MPR) mg/kg dose of GF120918 in comparison to mice pretreated with vehicle (24 ± 14% MPR) or mice receiving GF120918 without DPDPE (12 ± 8% MPR). A significant difference (p < 0.01) in brain tissue DPDPE concentration also was observed among treatment groups [25 ± 6 ng/g (vehicle), 37 ± 11 ng/g (25 mg/kg GF120918), 70 ± 8 ng/g (250 mg/kg GF120918)]. In contrast, blood DPDPE concentrations were not statistically different between groups (678 ± 66, 677 ± 130, and 818 ± 236 ng/ml for vehicle, GF120918 [25 mg/kg], and GF120918 [250 mg/kg], respectively). A single 100-mg/kg i.p. dose of (+)verapamil increased the brain:blood DPDPE concentration ratio by ~70% relative to saline-treated control mice (0.139 ± 0.021 vs. 0.0814 ± 0.0130, p < 0.01), a change in partitioning similar to that observed with the low dose of GF120918. These data provide further support for a P-gp-based mechanism of brain:blood DPDPE distribution. Conclusions. The present study demonstrates that GF120918 modulates blood-brain disposition and antinociception of DPDPE. Coadministration of a P-gp inhibitor with DPDPE may improve the pharmacologic activity of this opioid peptide.