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Excitatory amino acids play an important role in morphine tolerance. Recently, we demonstrated that a single morphine challenge induces an increase in spinal cerebrospinal fluid excitatory amino acid concentrations in morphine-tolerant rats, and that dexamethasone inhibits the development of morphine tolerance. We further examined the effect of intrathecal dexamethasone infusion on the development of morphine tolerance and on expression of the intracellular glutamate metabolizing enzymes, glutamate dehydrogenase and glutamine synthetase, in the spinal cord.Male Wistar rats, implanted with an intrathecal catheter, were divided into four groups that were infused for 5 days with intrathecal morphine (15 μg/h), saline (1 μL/h), dexamethasone (2 μg/h), or dexamethasone (2 μg/h) plus morphine (15 μg/h). On Day 5, the spinal cords were removed and prepared for Western blot analysis of glutamate dehydrogenase and glutamate synthetase.Glutamate dehydrogenase and glutamate synthetase concentrations were downregulated in the morphine-tolerant rat spinal cords. Concurrent infusion of dexamethasone attenuated morphine tolerance and the associated glutamate dehydrogenase and glutamate synthetase downregulation.Intrathecal dexamethasone attenuates long-term morphine infusion-induced glutamate dehydrogenase and glutamate synthetase downregulation and antinociceptive tolerance.