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 approximately 145 days). Intravenous infusion of morphine to the fetus resulted in dual actions on fetal plasma glucose, with hypoglycemia after 1.2 mg/hr (F3,16 = 6.02; P = .006; n = 5) and hyperglycemia after 5.0 mg/hr (F3,16 = 5.58; P = .008; n = 5). Significant increase in plasma lactate concentration also was found after 5.0 mg/hr (F3, 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-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (100 micrograms/hr i.c.v., n = 6), resulted in a significant increase in both plasma glucose (F3,20 = 11.50; P = .001) and lactate (F3,20 = 3.77; P = .007) concentrations. In contrast, the delta-selective agonists, [D-Pen2,D-Pen5]-enkephalin (30 and 100 micrograms/hr i.c.v.) and [D-Ala2]-deltorphin I (0.3 and 1.0 micrograms/hr i.c.v.) had no effect on plasma glucose or lactate levels. Similarly, Dynorphin A(1-13) (160 and 480 micrograms/hr i.c.v.) and U50,488H [trans-(+/-)-3,4-dichloro-N-methyl-[2-(1-pyrrolidinyl)-cyclohexyl] benzeneacetamide] (200 micrograms/hr i.c.v.) also had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)