Meijerink W J, Molina P E, Lang C H, Abumrad N N
Department of Surgery, State University of New York, Stony Brook 11794-8191.
Brain Res. 1996 Jan 8;706(1):123-8. doi: 10.1016/0006-8993(95)01205-2.
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.
以往的研究表明，兴奋性氨基酸参与了吗啡的镇痛和成瘾特性。然而，它们在吗啡诱导的葡萄糖代谢改变中的作用尚不清楚。本研究评估了NMDA受体激活对清醒、不受束缚、长期插管大鼠吗啡诱导的激素和代谢改变的影响。在用NMDA受体拮抗剂MK-801（0.25mg/kg，动脉内注射）或等体积（1.5ml）无菌生理盐水（0.9%）预处理15分钟后，通过静脉注射[3-3H]葡萄糖的首剂量恒定输注来评估大鼠的全身葡萄糖通量，随后进行脑室内注射H2O（对照组；5微升）或硫酸吗啡（80微克）。注射H2O的大鼠的代谢和激素参数未发现显著改变。脑室内注射吗啡可使血浆葡萄糖浓度升高（60%）、肝脏葡萄糖生成（Ra；60%）和全身葡萄糖利用（Rd；53%）增加，但未改变葡萄糖代谢清除率（MCR）。单独使用MK-801会导致短暂性高血糖（25%）、刺激葡萄糖Ra（60%）和葡萄糖Rd（53%），并使MCR显著升高（30%）。MK-801预处理可减轻吗啡诱导的高血糖以及葡萄糖Ra和Rd的增加。吗啡可使肾上腺素（4倍）、去甲肾上腺素（2倍）和皮质酮（67%）的血浆浓度升高；然而，未检测到血浆胰岛素和胰高血糖素的改变。MK-801预处理可减轻吗啡诱导的皮质酮和去甲肾上腺素的升高，并使胰岛素浓度显著升高。这些结果表明，NMDA受体的激活促成了吗啡诱导的高血糖和激素改变。此外，这种反应似乎部分由交感神经传出激活和胰岛素释放抑制介导，而抑制NMDA受体可使其减弱。
