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

N-Methyl-D-aspartate (NMDA) receptor antagonists and nitricoxide synthase (NOS) inhibitors inhibit morphine tolerance.In the present study, a lumbar subarachnoid polyethylene (PE₁₀)catheter was implanted for drug administration to study alterationsin NMDA receptor activity and NOS protein expression in a morphine-tolerantrat 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-dibenzoa,d]cyclohepten-5,10-iminemaleate (MK-801) (10 µg h^–1 i.t.) with morphinewas used to inhibit the development of morphine tolerance. Lumbarspinal cord segments were removed and prepared for ³H]MK-801binding assays and NOS western blotting. The binding affinityof ³H]MK-801 was higher in spinal cords of morphine-tolerantrats (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 analysisshowed that constitutive expression of neuronal NOS (nNOS) proteinin the morphine-tolerant group was twice that in the controlgroup. This up-regulation was partially prevented by MK-801.The results suggest that morphine tolerance affects NMDA receptorbinding activity and increases nNOS expression in the rat spinalcord. Br J Anaesth 2000; 85: 587–91 ^* Corresponding author