title: Increased CNS uptake and enhanced antinociception of morphine-6-glucuronide in rats after inhibition of P-glycoprotein.
abstract: Morphine-6-glucuronide (M6G) is a substrate of P-glycoprotein (P-gp), which forms an outward transporter at the blood-brain barrier. Inhibition of P-gp may therefore be expected to cause increased CNS uptake of M6G. We directly assessed the spinal concentrations of M6G and its antinociceptive effects in rats following pharmacological inhibition of P-gp. Spinal cord tissue concentrations of M6G were assessed by microdialysis with probes transversally implanted through the dorsal horns of the spinal cord at level L4. Ten rats received M6G intravenously (0.018 mg/kg loading dose plus 0.00115 mg/kg/min for an 8-h infusion), five of them together with PSC833 to inhibit P-gp (32-h infusion, starting 24 h before the addition of M6G). Antinociceptive effects were explored by means of formalin tests. After having obtained evidence for enhanced CNS uptake and antinociception of M6G in the presence of PSC833, additional behavioural experiments were performed in another 32 rats to assess the dose dependency of the antinociceptive effects of M6G either with or without PSC833 in comparison with both PSC833 alone and placebo. Inhibition of P-gp increased the M6G concentrations in the spinal cord approximately three-fold whereas the plasma concentrations were increased only by a factor of 1.4, which resulted in a more than doubled spinal cord/plasma concentration ratio (from 0.08 +/- 0.03 for M6G alone to 0.17 +/- 0.08 for M6G plus PSC833). Antinociceptive effects of M6G were significantly enhanced by inhibition of P-gp. Inhibition of P-gp alters the transport of M6G across the blood-brain barrier, resulting in enhanced spinal cord uptake and enhanced antinociception.
authors.affiliation: pharmazentrum frankfurt, Department of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany. j.loetcsh@em.uni-frankfurt.de
authors.forename: Jörn
authors.initials: J
authors.lastname: Lötsch
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Schmidt
authors.forename: Gregor
authors.initials: G
authors.lastname: Vetter
authors.forename: Helmut
authors.initials: H
authors.lastname: Schmidt
authors.forename: Ellen
authors.initials: E
authors.lastname: Niederberger
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.forename: Irmgard
authors.initials: I
authors.lastname: Tegeder
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis / Q000037:antagonists & inhibitors*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D015153:Blotting, Western; D002490:Central Nervous System / Q000187:drug effects* / Q000378:metabolism; D003524:Cyclosporins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde; D007262:Infusions, Intravenous; D007668:Kidney / Q000737:chemistry; D008161:Lumbosacral Region; D008297:Male; D017551:Microdialysis; D009022:Morphine Derivatives / Q000493:pharmacokinetics*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy; D010147:Pain Measurement / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D009022:Morphine Derivatives; D005557:Formaldehyde; C035349:morphine-6-glucuronide; C070272:valspodar