Lötsch Jörn, Schmidt Rodolfo, Vetter Gregor, Schmidt Helmut, Niederberger Ellen, Geisslinger Gerd, Tegeder Irmgard
pharmazentrum frankfurt, Department of Clinical Pharmacology, Johann Wolfgang Goethe-University, Frankfurt, Germany.
J Neurochem. 2002 Oct;83(2):241-8. doi: 10.1046/j.1471-4159.2002.01177.x.
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.
吗啡 - 6 - 葡萄糖醛酸苷（M6G）是P - 糖蛋白（P - gp）的底物，P - gp在血脑屏障处形成外向转运体。因此，预计抑制P - gp会导致M6G的中枢神经系统摄取增加。我们直接评估了在对P - gp进行药理学抑制后大鼠脊髓中M6G的浓度及其抗伤害感受作用。通过微透析评估M6G在脊髓组织中的浓度，微透析探针经横向植入L4水平脊髓背角。10只大鼠静脉注射M6G（0.018 mg/kg负荷剂量加0.00115 mg/kg/min持续8小时输注），其中5只同时给予PSC833以抑制P - gp（32小时输注，在加入M6G前24小时开始）。通过福尔马林试验探究抗伤害感受作用。在获得证据表明存在PSC833时M6G的中枢神经系统摄取和抗伤害感受增强后，对另外32只大鼠进行了额外的行为实验，以评估与单独使用PSC833和安慰剂相比，有或没有PSC833时M6G抗伤害感受作用的剂量依赖性。抑制P - gp使脊髓中M6G的浓度增加约三倍，而血浆浓度仅增加1.4倍，这导致脊髓/血浆浓度比增加了一倍多（从单独使用M6G时的0.08±0.03增加到M6G加PSC833时的0.17±0.08）。抑制P - gp显著增强了M6G的抗伤害感受作用。抑制P - gp改变了M6G跨血脑屏障的转运，导致脊髓摄取增加和抗伤害感受增强。
