title: The influence of inhibition of probenecid sensitive transporters on the central nervous system (CNS) uptake and the antinociceptive activity of morphine-6-glucuronide in rats.
abstract: In light of a recent demonstration that probenecid enhanced the central nervous system (CNS) uptake of morphine-3-glucuronide (M3G), we investigated the consequences of probenecid co-administration for the spinal cord concentrations and antinociceptive effects of morphine-6-glucuronide (M6G) in rats. Spinal cord tissue concentrations of M6G were assessed by in-vivo microdialysis. Ten rats were administered M6G by intravenous infusion for 8 h, five of them additionally received an infusion of probenecid. Antinociceptive effects of M6G were assessed by means of formalin tests during the 8th h of the M6G infusion in another five rats that received M6G together with probenecid. Five additional rats per groups received probenecid only, M6G only and placebo. The inhibition of probenecid-sensitive transporters caused a raise in both plasma (statistically significant) and spinal cord tissue (not statistically significant) concentrations of M6G by a factor of 1.3, without affecting the tissue to plasma concentration ratio of M6G (0.0812 +/- 0.034 for M6G alone, 0.0824 +/- 0.021 for M6G plus probenecid). Co-administration of probenecid with M6G resulted in a significant reduction of the number of flinches by a factor of 2.5 as compared to M6G alone. The study showed that probenecid sensitive transporters play a role for the CNS concentrations of M6G via an increase of its plasma concentrations, but the effect of probenecid co-administration is small as compared to the reported effects on the CNS concentrations of M3G in rats.
authors.affiliation: pharmazentrum frankfurt, Department of Clinical Pharmacology, Johann Wolfgang Goethe-University, Theodor Stern Kai 7, D-60590 Frankfurt am Main, Germany. j.loetsch@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: Carsten
authors.initials: C
authors.lastname: Skarke
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: D000700:Analgesics / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism*; D004359:Drug Therapy, Combination; D008297:Male; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009022:Morphine Derivatives / Q000378:metabolism* / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D011339:Probenecid / Q000378:metabolism* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
chemical_list: D000700:Analgesics; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D009022:Morphine Derivatives; C035349:morphine-6-glucuronide; D011339:Probenecid