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Abstract. This study was designed to assess the effects of morphine sulfate on glucose kinetics and on glucoregulatory hormones in conscious overnight fasted dogs. One group of experiments established a dose-response range. We studied the mechanisms of morphine-induced hyperglycemia in a second group. We also examined the effect of low dose morphine on glucose kinetics independent of changes in the endocrine pancreas by the use of somatostatin plus intraportal replacement of basal insulin and glucagon.In the dose-response group, morphine at 2 mg/h did not change plasma glucose, while morphine at 8 and 16 mg/h caused a hyperglycemic response. In the second group of experiments, morphine (16 mg/h) caused an increase in plasma glucose from a basal 99±3 to 154±13 mg/dl (P < 0.05). Glucose production peaked at 3.9±0.7 vs. 2.5±0.2 mg/kg per min basally, while glucose clearance declined to 1.7±0.2 from 2.5±0.1 ml/kg per min (both P < 0.05). Morphine increased epinephrine (1400±300 vs. 62±8 pg/ml), norepinephrine (335±66 vs. 113±10 pg/ml), glucagon (242±53 vs. 74±14 pg/ ml), insulin (30±9 vs. 10±2 MU/ml), cortisol (11.1±3.3 vs. 0.9±0.2 Ag/dl), and plasma beta-endorphin (88±27 vs. 23±6 pg/ml); all values P < 0.05 compared with basal. These results show that morphine-induced hyperglycemia results from both stimulation of glucose production as well as inhibition of glucose clearance. These changes can be explained by rises in epinephrine, glucagon, and cortisol. These in turn are part ofa widespread catabolic response initiated by high dose morphine that involves activation of the sympathetic nervous system, the endocrine pancreas, and the pituitary-adrenal axis.Address reprint requests to Dr. Abumrad.Receivedfor publication 21 November 1983 and in revisedform 21June 1984.Also, we report the effect of a 2 mg/h infusion of morphine on glucose kinetics when the endocrine pancreas is clamped at basal levels. Under these conditions, morphine exerts a hypoglycemic effect (25% fall in plasma glucose, P < 0.05) that is due to inhibition of glucose production (by 25-43%, P < 0.05). The hypoglycemia was independent of detectable changes in insulin, glucagon, epinephrine and cortisol, and was not reversed by concurrent infusion of a slight molar excess of naloxone. Therefore, we postulate that the hypoglycemic effect of morphine results from the interaction of the opiate with non-mu receptors either in the liver or the central nervous system.

The present study examines the effect of glutamine infusion on the interorgan fluxes of glutamine, alanine, urea, and ammonia with progressive fasting. Experiments were carried out in two groups of conscious dogs with catheters previously implanted in an artery and in the hepatic, portal, and renal veins. Group I (n = 12) was fasted for 24 h, and group II (n = 10) was fasted for 96 h. On the day of the study, seven animals of group I and five of group II received a constant infusion of glutamine (3.0 mumol . kg-1 . min-1) for 1 h, and the rest (controls) received saline. Four-day fasting produced ketosis with a compensated metabolic acidosis. The demand for glutamine by the kidneys and gut increased, and the liver switched from net glutamine utilization to that of net production. The kidneys (33%) and gut (230%) increased their production of ammonia, while their release of alanine decreased. The estimated efflux of glutamine by skeletal muscle, however, did not change. All of the infused glutamine was cleared by the splanchnic and renal tissues. In group I, there was increased gut production of alanine, which was matched by increased hepatic alanine uptake and urea production. No such changes were observed in Group II. There was, however, an increase in hepatic uptake of ammonia. Finally, glutamine infusion did not alter glutamine or alanine output by skeletal muscle in group I, while it decreased efflux of alanine but not that of glutamine in group II. The data emphasize the complex interdependence of the liver, gut, kidneys, and skeletal muscle in nitrogen sparing.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract. The effect of human fl-endorphin (h(3E) infusion (0.2 mg/h) on glucose homeostasis was studied in 10 conscious overnight fasted dogs in which endocrine pancreatic function was fixed at basal levels with somatostatin plus intraportal replacement of basal insulin and glucagon.h#E caused a fall in plasma glucose from 107±5 to 76±6 mg/dl by 3 h (P < 0.01). This was due to a 25% fall in tracer-determined glucose production (Ra; P < 0.01). A significantly larger fall in Ra was observed in four dogs in which hypoglycemia was prevented by use of an exogenous glucose infusion (45 vs. 25%, P < 0.05). These changes occurred in the absence of changes in circulating levels of insulin, glucagon, epinephrine, norepinephrine, and cortisol.We conclude that the naturally occurring opioid peptide, f3-endorphin, inhibits glucose production by the liver in vivo. This appears to be a direct effect of the opioid on the liver, since the inhibition took place in the absence ofchanges in the other hormones measured. These results suggest that endorphins act on glucose homeostasis in a complex way, both by affecting other glucoregulatory hormones as demonstrated elsewhere, and by directly modulating hepatic glucose production as shown here. IntroductionThe role of opioids in glucoregulation is not completely clear. Several reports (1-3) have shown that opioids can cause hy-

The effects of centrally administered beta-endorphins on glucose homeostasis in the conscious dog were studied. Intracerebroventricular administration of beta-endorphin (0.2 mg/h) caused a 70% increase in plasma glucose. The mechanism of the hyperglycemia was twofold: there was an early increase in glucose production and a late inhibition of glucose clearance. These changes are explained by marked increases in plasma epinephrine (30-fold) and norepinephrine (6-fold) that occurred during infusion of beta-endorphin. Central administration of beta-endorphin also resulted in increased levels of adrenocorticotropic hormone and cortisol. In addition there was an increase in plasma insulin but no increase in plasma glucagon. Intravenous administration of beta-endorphin did not alter glucose homeostasis. Intracerebroventricular administration of acetylated beta-endorphin did not perturb glucose kinetics or any of the hormones that changed during infusion of the unacetylated peptide. We conclude that beta-endorphin acts centrally to cause hyperglycemia by stimulating sympathetic outflow and the pituitary-adrenal axis. Acetylation of beta-endorphin abolishes the in vivo activity of the peptide.