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

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 administr ation to study alterations in NMDA receptor activity and NOS protein expres sion in a morphine-tolerant rat spinal model. Antinociceptive tolerance was induced by intrathecal (i.t.) morphine infusion (10 mu g h(-1)) for 5 days . Co-administered (+)-5-methyl-10,11-dihydro-H-5-dibenzo[a,d]cyclohepten-5, 10-imine maleate (MK-801) (10 mu g h(-1) i.t.) with morphine was used to in hibit the development of morphine tolerance. Lumbar spinal cord segments we re removed and prepared for [H-3]MK-801 binding assays and NOS western blot ting. The binding affinity of [H-3]MK-801 was higher in spinal cords of mor phine-tolerant rats (mean (SEM) K-D=0.41 (0.09) nM) than in control rats (1 .50 (0.13) nM). There was no difference in B-max. Western blot analysis sho wed that constitutive expression of neuronal NOS (nNOS) protein in the morp hine-tolerant group was twice that in the control group. This up-regulation was partially prevented by MK-801. The results suggest that morphine toler ance affects NMDA receptor binding activity and increases nNOS expression i n the rat spinal cord.