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

Opioids have long been known to influence glucose homeostasis in the a dult. However, their role in modulating glucose regulation in the fetu s is not known. The objectives of this study were to determine the eff ects of morphine on fetal plasma glucose levels and to ascertain the r ole of opioid receptor subtypes in fetal glucose homeostasis. The stud ies were carried out in 38 unanesthetized fetal sheep (123-142 days) ( term being similar to 145 days). Intravenous infusion of morphine to t he fetus resulted in dual actions on fetal plasma glucose, with hypogl ycemia after 1.2 mg/hr (F-3,F-16 = 6.02; P = .006; n = 5) and hypergly cemia 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/h r (F-3,F-16 = 5.25; P = .010). Both hypoglycemia and hyperglycemia wer e antagonized by i.v. naloxone, indicating both were mediated by speci fic 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 sign ificant increase in both plasma glucose (F-3,F-20 = 11.50; P = .001) a nd lactate (F-3,F-20 = 3.77; P = .007) concentrations. in contrast, th e 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, Dynorp hin 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 g lucose and lactate levels. These results suggest that the effects of o pioids on fetal glucose homeostasis are dependent on dose and receptor -selectivity.