CONTRIBUTION OF EXCITATORY AMINO-ACIDS TO MORPHINE-INDUCED METABOLIC ALTERATIONS

Previous studies have indicated that excitatory amino acids are involv ed in the analgesic and addictive properties of morphine. However, the ir role in the morphine-induced alterations in glucose metabolism is n ot known. This study assessed the contribution of NMDA receptor activa tion to the morphine-induced hormonal and metabolic alterations in con scious unrestrained chronically catheterized rats. Whole body glucose flux was assessed with a primed constant intravenous infusion of [3-H- 3]glucose in rats pretreated with the NMDA-receptor antagonist MK-801 (0.25 mg/kg, intraarterial) or an equal volume (1.5 ml) of sterile sal ine (0.9%) administered 15 min prior to i.c.v. injection of H2O (Con; 5 mu l) or morphine sulfate (80 mu g). No significant alterations were noted in metabolic and hormonal parameters of H2O injected rats. i.c. v. morphine increased the plasma glucose concentration (60%), hepatic glucose production (R(a); 60%) and whole body glucose utilization (R(d ); 53%), but did not alter the glucose metabolic clearance rate (MCR). MK-801 alone resulted in transient hyperglycemia (25%), stimulation o f glucose R(a) (60%) and glucose R(d) (53%), and a significant (30%) i ncrease in MCR. MK-801 pretreatment blunted the morphine-induced hyper glycemia and the increased glucose R(a) and R(d). Morphine increased t he plasma concentration of epinephrine (4-fold), norepinephrine (2-fol d) and corticosterone (67%); however, no alterations in plasma insulin and glucagon were detected. MK-801 pretreatment, blunted the morphine -induced increase in corticosterone and norepinephrine, and elicited a significant rise in insulin concentrations. These results indicate th at activation of the NMDA receptors contributes to the morphine-induce d hyperglycemia and hormonal alterations. Furthermore, this response a ppears partially mediated by activation of sympathetic outflow and sup pression of insulin release, which is blunted by inhibition of NMDA re ceptors.