title: Pluronic p85 block copolymer enhances opioid peptide analgesia.
abstract: 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-Pen(2),D-Pen(5)]-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 (125)I-DPDPE and [(3)H]morphine at 0.01% (p < 0.01) and 1.0% (p < 0.01 and p < 0.05, respectively). Cyclosporin-A coadministration with (125)I-DPDPE and [(3)H]morphine increased cellular uptake (p < 0.01 and p < 0.05, respectively). (125)I-DPDPE and [(3)H]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 (125)I-DPDPE and [(3)H]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.
authors.affiliation: Department of Pharmacology, College of Medicine, The University of Arizona, Tucson, AZ 85724, USA.
authors.forename: Ken A
authors.initials: KA
authors.lastname: Witt
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
authors.forename: Richard D
authors.initials: RD
authors.lastname: Egleton
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Davis
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D002196:Capillaries / Q000187:drug effects / Q000378:metabolism; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D004745:Enkephalins / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009020:Morphine / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects*; D011060:Poloxalene / Q000737:chemistry / Q000494:pharmacology*; D011930:Reaction Time / Q000187:drug effects; D012997:Solvents
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000701:Analgesics, Opioid; D004745:Enkephalins; D012997:Solvents; C422648:pluronic block copolymer p85; D009020:Morphine; C053673:biphalin; D020881:Enkephalin, D-Penicillamine (2,5)-; D011060:Poloxalene