title: Contribution of excitatory amino acids to morphine-induced metabolic alterations.
abstract: Previous studies have indicated that excitatory amino acids are involved in the analgesic and addictive properties of morphine. However, their role in the morphine-induced alterations in glucose metabolism is not known. This study assessed the contribution of NMDA receptor activation to the morphine-induced hormonal and metabolic alterations in conscious unrestrained chronically catheterized rats. Whole body glucose flux was assessed with a primed constant intravenous infusion of [3-3H]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 saline (0.9%) administered 15 min prior to i.c.v. injection of H2O (Con; 5 microliters) or morphine sulfate (80 micrograms). 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 (Ra; 60%) and whole body glucose utilization (Rd; 53%), but did not alter the glucose metabolic clearance rate (MCR). MK-801 alone resulted in transient hyperglycemia (25%), stimulation of glucose Ra (60%) and glucose Rd (53%), and a significant (30%) increase in MCR. MK-801 pretreatment blunted the morphine-induced hyperglycemia and the increased glucose Ra and Rd. Morphine increased the plasma concentration of epinephrine (4-fold), norepinephrine (2-fold) 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 that activation of the NMDA receptors contributes to the morphine-induced hyperglycemia and hormonal alterations. Furthermore, this response appears partially mediated by activation of sympathetic outflow and suppression of insulin release, which is blunted by inhibition of NMDA receptors.
authors.affiliation: Department of Surgery, State University of New York, Stony Brook 11794-8191.
authors.forename: W J
authors.initials: WJ
authors.lastname: Meijerink
authors.forename: P E
authors.initials: PE
authors.lastname: Molina
authors.forename: C H
authors.initials: CH
authors.lastname: Lang
authors.forename: N N
authors.initials: NN
authors.lastname: Abumrad
mesh_terms: D000818:Animals; D018846:Excitatory Amino Acids / Q000502:physiology*; D005947:Glucose / Q000378:metabolism*; D006728:Hormones / Q000378:metabolism; D007276:Injections, Intraventricular; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D009020:Morphine / Q000494:pharmacology*; D016202:N-Methylaspartate / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists*
chemical_list: D018846:Excitatory Amino Acids; D006728:Hormones; D008112:Liver Glycogen; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D009020:Morphine; D005947:Glucose