OPIOID MODULATION OF FETAL GLUCOSE-HOMEOSTASIS - ROLE OF RECEPTOR SUBTYPES

Opioids have long been known to influence glucose homeostasis in the adult. However, their role in modulating glucose regulation in the fetus is not known. The objectives of this study were to determine the effects of morphine on fetal plasma glucose levels and to ascertain the role of opioid receptor subtypes in fetal glucose homeostasis. The studies were carried out in 38 unanesthetized fetal sheep (123-142 days) (term being similar to 145 days). Intravenous infusion of morphine to the fetus resulted in dual actions on fetal plasma glucose, with hypoglycemia after 1.2 mg/hr (F-3,F-16 = 6.02; P = .006; n = 5) and hyperglycemia after 5.0 mg/hr (F-3,F-16 = 5.58; P = .008; n = 5). Significant increase in plasma lactate concentration also was found after 5.0 mg/hr (F-3,F-16 = 5.25; P = .010). Both hypoglycemia and hyperglycemia were antagonized by i.v. naloxone, indicating both were mediated by specific opioid receptors. The mu-selective agonist, [D-Ala(2), N-Me-Phe(4),Gly(5)-ol]-enkephalin (100 mu g/hr i.c.v., n = 6), resulted in a significant increase in both plasma glucose (F-3,F-20 = 11.50; P = .001) and lactate (F-3,F-20 = 3.77; P = .007) concentrations. in contrast, the delta-selective agonists, [D-Pen(2),D-Pen(5)]-enkephalin (30 and 100 pg/hr i.c.v.) and [D-Ala(2)]-deltorphin I (0.3 and 1.0 mu g/hr i.c.v.) had no effect on plasma glucose or lactate levels. Similarly, Dynorphin A(1-13) (160 and 480 mu g/hr i.c.v.) and U50,488H {trans-(+/-)-3,4-dichloro-N-methyl-[2-(1- pyrrolidinyl)-cyclohexyl]benzeneacetamide} (200 mu g/hr i.c.v.) also had no effect. The effects of morphine and [D-Ala(2),N-Me-Phe(4),Gly(5)-ol]-enkephalin on fetal plasma glucose and lactate levels cannot be accounted for by changes in maternal plasma glucose and lactate levels. These results suggest that the effects of opioids on fetal glucose homeostasis are dependent on dose and receptor-selectivity.