Vol. 303, Issue 2, 760-767, November 2002

Pluronic P85 Block Copolymer Enhances Opioid Peptide Analgesia

Ken A. Witt, Jason D. Huber, Richard D. Egleton and Thomas P. Davis

Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, Arizona

Peptide-based drug development is a rapidly growing field within pharmaceutical research. Nevertheless, peptides have found limited clinical use due to several physiological and pathological factors. Pluronic block copolymers represent a growing technology with the potential to enhance efficacy of peptide therapeutics. This investigation assesses Pluronic P85 (P85) and its potential to enhance opioid peptide analgesia. Two opioid peptides, [D-Pen²,D-Pen⁵]-enkephalin (DPDPE) and biphalin, were examined as to the benefits of P85 coadministration, above (1.0%) and below (0.01%) the critical micelle concentration, with morphine as a nonpeptide control. P85 was examined in vitro to assess blood-brain barrier uptake in association with P-glycoprotein effect, DPDPE and morphine being P-glycoprotein substrates. P85 coadministration with DPDPE and biphalin showed increased (p < 0.01) analgesia with both 0.01 and 1.0% P85. Morphine showed increased (p < 0.01) analgesia with 0.01% P85 only. This increase in analgesia is due to both an increase in peak effect, as well as a prolongation of effect. P85 increased cellular uptake of ¹²⁵I-DPDPE and [³H]morphine at 0.01% (p < 0.01) and 1.0% (p < 0.01 and p < 0.05, respectively). Cyclosporin-A coadministration with ¹²⁵I-DPDPE and [³H]morphine increased cellular uptake (p < 0.01 and p < 0.05, respectively). ¹²⁵I-DPDPE and [³H]morphine coadministered with 0.01% P85 and cyclosporin-A increased cellular uptake compared with control (p < 0.01) and compared with cyclosporin-A coadministration without P85 (p < 0.01 and p < 0.05, respectively). This indicates that, in addition to P-gp inhibition, 0.01% P85 increased ¹²⁵I-DPDPE and [³H]morphine uptake. In our examination, we determined that P85 enhanced the analgesic profile of biphalin, DPDPE, and morphine, both above and below the critical micelle concentration.