Wong C S, Hsu M M, Chou Y Y, Tao P L, Tung C S
Department of Anesthesiology, National Defense Medical Center, Taipei, Taiwan.
Br J Anaesth. 2000 Oct;85(4):587-91. doi: 10.1093/bja/85.4.587.
N-Methyl-D-aspartate (NMDA) receptor antagonists and nitric oxide synthase (NOS) inhibitors inhibit morphine tolerance. In the present study, a lumbar subarachnoid polyethylene (PE10) catheter was implanted for drug administration to study alterations in NMDA receptor activity and NOS protein expression in a morphine-tolerant rat spinal model. Antinociceptive tolerance was induced by intrathecal (i.t.) morphine infusion (10 micrograms h-1) for 5 days. Co-administered (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (10 micrograms h-1 i.t.) with morphine was used to inhibit the development of morphine tolerance. Lumbar spinal cord segments were removed and prepared for [3H]MK-801 binding assays and NOS western blotting. The binding affinity of [3H]MK-801 was higher in spinal cords of morphine-tolerant rats (mean (SEM) KD = 0.41 (0.09) nM) than in control rats (1.50 (0.13) nM). There was no difference in Bmax. Western blot analysis showed that constitutive expression of neuronal NOS (nNOS) protein in the morphine-tolerant group was twice that in the control group. This up-regulation was partially prevented by MK-801. The results suggest that morphine tolerance affects NMDA receptor binding activity and increases nNOS expression in the rat spinal cord.
N-甲基-D-天冬氨酸（NMDA）受体拮抗剂和一氧化氮合酶（NOS）抑制剂可抑制吗啡耐受性。在本研究中，植入腰椎蛛网膜下腔聚乙烯（PE10）导管用于给药，以研究吗啡耐受大鼠脊髓模型中NMDA受体活性和NOS蛋白表达的变化。通过鞘内（i.t.）输注吗啡（10微克/小时）5天诱导抗伤害感受耐受性。与吗啡联合给予（+）-5-甲基-10,11-二氢-5H-二苯并[a,d]环庚烯-5,10-亚胺马来酸盐（MK-801）（10微克/小时i.t.）以抑制吗啡耐受性的发展。取出腰段脊髓节段，准备用于[3H]MK-801结合测定和NOS免疫印迹分析。[3H]MK-801在吗啡耐受大鼠脊髓中的结合亲和力（平均（SEM）KD = 0.41（0.09）nM）高于对照大鼠（1.50（0.13）nM）。最大结合量（Bmax）无差异。免疫印迹分析显示，吗啡耐受组中神经元型NOS（nNOS）蛋白的组成性表达是对照组的两倍。MK-801可部分阻止这种上调。结果表明，吗啡耐受性影响NMDA受体结合活性，并增加大鼠脊髓中nNOS的表达。
