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British Journal of Anaesthesia, 2000, Vol. 85, No. 4 587-591
© 2000 The Board of Management and Trustees of the British Journal of Anaesthesia

Morphine tolerance increases [3H]MK-801 binding affinity and constitutive neuronal nitric oxide synthase expression in rat spinal cord

Chih-Shung Wong1,*, Ming-Man Hsu1, Yen-Yen Chou1, Pao-Luh Tao2 and Che-Se Tung3

1Department of Anesthesiology, National Defense Medical Center and Tri-Service General Hospital, 2Departments of Pharmacology and 3Physiology and Biophysics, National Defense Medical Center, Taipei, Taiwan

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 µg h–1) for 5 days. Co-administered (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) (10 µg 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.

Br J Anaesth 2000; 85: 587–91

* Corresponding author


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