Zong J, Pollack G M
Division of Drug Delivery and Disposition, School of Pharmacy, University of North Carolina at Chapel Hill 27599-7360, USA.
Pharm Res. 2000 Jun;17(6):749-53. doi: 10.1023/a:1007546719287.
Previous studies have suggested that P-glycoprotein (P-gp) modulates opioid antinociception for selected mu-and delta-agonists. This study was undertaken to assess morphine antinociception in mice lacking the mdr1a gene for expression of P-gp in the CNS.
Morphine (n = 4-5/group) was administered as a single s.c. dose to mdr1a(-/-) mice (3-5 mg/kg) or wild-type FVB controls (8-10 mg/kg). Tail-flick response to radiant heat, expressed as percent of maximum response (%MPR), was used to determine the antinociceptive effect of morphine. Concentrations in serum, brain tissue, and spinal cord samples obtained immediately after the tail-flick test were determined by HPLC with fluorescence detection. Parallel experiments with R(+)-verapamil, a chemical inhibitor of P-gp, also were performed to further investigate the effect of P-gp on morphine-associated antinociception.
Morphine-associated antinociception was increased significantly in the mdr1a(-/-) mice. The ED50 for morphine was > 2-fold lower in mdr1a(-/-) (3.8+/-0.2 mg/kg) compared to FVB (8.8+/-0.2 mg/kg) mice. However, the EC50 derived from the brain tissue was similar between the two mouse strains (295 ng/g vs. 371 ng/g). Pretreatment with R(+)-verapamil produced changes similar to those observed in gene-deficient mice. P-gp does not appear to affect morphine distribution between spinal cord and blood, as the spinal cord:serum morphine concentration ratio was similar between gene-deficient and wild-type mice (0.47+/-0.03 vs. 0.56+/-0.04, p>0.05).
The results of this study are consistent with the hypothesis that P-gp attenuates the antinociceptive action of morphine by limiting the brain:blood partitioning of the opioid.
以往研究表明，P-糖蛋白（P-gp）可调节特定μ-和δ-激动剂的阿片类药物镇痛作用。本研究旨在评估缺乏中枢神经系统中P-gp表达的mdr1a基因的小鼠对吗啡的镇痛作用。
将吗啡（每组4-5只）以单次皮下注射的方式给予mdr1a（-/-）小鼠（3-5mg/kg）或野生型FVB对照小鼠（8-10mg/kg）。用甩尾对辐射热的反应，以最大反应百分比（%MPR）表示，来确定吗啡的镇痛效果。甩尾试验后立即采集的血清、脑组织和脊髓样本中的浓度通过高效液相色谱荧光检测法测定。还进行了与P-gp化学抑制剂R（+）-维拉帕米的平行实验，以进一步研究P-gp对吗啡相关镇痛作用的影响。
mdr1a（-/-）小鼠中吗啡相关的镇痛作用显著增强。与FVB小鼠（8.8±0.2mg/kg）相比，mdr1a（-/-）小鼠中吗啡的半数有效剂量（ED50）低2倍以上（3.8±0.2mg/kg）。然而，两种小鼠品系脑组织中的半数有效浓度（EC50）相似（295ng/g对371ng/g）。用R（+）-维拉帕米预处理产生的变化与基因缺陷小鼠中观察到的变化相似。P-gp似乎不影响吗啡在脊髓和血液之间的分布，因为基因缺陷小鼠和野生型小鼠的脊髓：血清吗啡浓度比相似（0.47±0.03对0.56±0.04，p>0.05）。
本研究结果与以下假设一致，即P-gp通过限制阿片类药物在脑与血之间的分配来减弱吗啡的镇痛作用。
