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

• Published in: Neuroscience letters Vol. 329; no. 2; pp. 145 - 148
• Main Authors: Lötsch, Jörn, Schmidt, Rodolfo, Vetter, Gregor, Schmidt, Helmut, Skarke, Carsten, Niederberger, Ellen, Geisslinger, Gerd, Tegeder, Irmgard
• Format: Journal Article
• Language: English
• Published: Shannon Elsevier Ireland Ltd 30.08.2002; Elsevier
• Subjects: Analgesics; Analgesics - metabolism; Analgesics - pharmacology; Animals; Biological and medical sciences; Central Nervous System - drug effects; Central Nervous System - metabolism; Drug Therapy, Combination; Male; Medical sciences; Membrane Transport Modulators; Membrane Transport Proteins - antagonists & inhibitors; Membrane Transport Proteins - metabolism; Microdialysis; Morphine Derivatives - metabolism; Morphine Derivatives - pharmacology; Morphine-6-glucuronide; Multidrug resistance protein; Neuropharmacology; Organic anion transporter polypeptide; Organic anion transporters; Pain; Pain Measurement - drug effects; Pain Measurement - methods; Pharmacokinetics; Pharmacology. Drug treatments; Probenecid - metabolism; Probenecid - pharmacology; Rats; Rats, Sprague-Dawley; Spinal Cord - drug effects; Spinal Cord - metabolism; Organic anion transporters; Pain; Microdialysis; Morphine-6-glucuronide; Multidrug resistance protein; Rats; Pharmacokinetics; Organic anion transporter polypeptide; Rat; Metabolite; Rodentia; Central nervous system; Morphine; Opiates; Narcotic analgesic; Vertebrata; Mammalia; Animal; Carrier protein; Probenecid
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/S0304-3940(02)00618-3

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.