Central opioid modulation of fetal cardiovascular function: role of mu- and delta-receptors

To investigate the role of mu- and delta-receptors in opioid modulation of fetal cardiovascular function, we compared the effects on fetal heart rate (FHR) and fetal blood pressure (FBP) of [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAGO, a mu-selective agonist), [D-Pen2,D-Pen5]-enkephalin (DPDPE, delta-selective agonist), and [D-Ala2,D-Leu5]-enkephalin (DADLE, a mixed mu- and delta-agonist) in 24 fetal lambs. All peptides were infused intracerebroventricularly at a constant rate for 1 h. Three to seven animals were studied at each of six dose levels ranging from 1.58 to 476 nmol/h. Saline infusion did not elicit any changes in FBP or FHR. DAGO caused a dose-dependent increase in FHR, with the peak response being 61.6 +/- 9.9% at the highest dose. The effects of DAGO on FBP were small (maximum being 11.1 +/- 3.4%) and did not reach statistical significance. In contrast, DPDPE did not induce any changes in either FHR or FBP over the same dose range, suggesting that delta-receptors do not play a role in opioid modulation of fetal cardiovascular function. The FHR response to DADLE was similar to DAGO in both dose-response and time-action characteristics. The finding that DADLE behaved like DAGO rather than DPDPE suggests that the opioid-induced fetal tachycardia may be mediated via mu 1-receptors. There was also evidence for rapid development of tolerance to the FHR response to both DAGO and DADLE, as demonstrated by the decline in FHR response by 45-50 min despite continuous peptide infusion.