The Contribution of δ1- and δ2-Opioid Receptors to Hypoxia-Induced Pial Artery Dilation in the Newborn Pig

Abstract

Previously, it has been observed that μ-opioid receptors contribute to while κ-opioid receptors oppose pial artery dilation in response to hypoxia. The present study was designed to investigate the contribution of δ₁- and δ₂-opioid receptor activation to hypoxia-induced pial vasodilation. Newborn pigs equipped with a closed cranial window were used to measure pial artery diameter and collect cortical periarachnoid CSF for assay of opioids. Hypoxia increased CSF leucine enkephalin (a δ-agonist) from 36 ± 6 to 113 ± 17 pg/ml (n = 5). Hypoxiainduced pial artery vasodilation was attenuated during moderate hypoxia (P_ao₂ ≈ 35 mm Hg), while this response was blunted during severe hypoxia (P_ao₂ ≈ 25 mm Hg), by the δ₁-opioid receptor antagonist 7-benzylidenenaltrexone (BNTX; 10⁻⁸ M) (23 ± 2 vs. 13 ± 2 and 34 ± 6 vs. 10 ± 3% for moderate and severe hypoxia in the absence and presence of BNTX, respectively; n = 5). In contrast, the δ₂-opioid receptor antagonist naltrindole (10⁻⁹ M) blunted pial vasodilation during moderate hypoxia, but only attenuated the vasodilator response during severe hypoxia (22 ± 2 vs. 8 ± 2 and 33 ± 4 vs. 23 ± 4% for moderate and severe hypoxia in the absence and presence of naltrindole, respectively; n = 5). Receptor selectivity experiments show that BNTX blocked responses to the δ₁-agonist DPDPE, whereas responses to the δ₂-agonist deltorphin II were unchanged (12 ± 3 vs. 2 ± 1% and 14 ± 4 vs. 14 ± 3% for DPDPE at 10⁻⁶ M and deltorphin II at 10⁻⁶ M in the absence and presence of BNTX; n = 5). Similarly, naltrindole blocked responses to deltorphin II, but responses to DPDPE were unchanged. These data indicate that δ₁-receptor activation contributes to both moderate and severe hypoxia-induced vasodilation, but the δ₁-receptors appear to be more important during severe hypoxia relative to δ₂-receptors. Additionally, these data show that δ₂-receptors primarily contribute to dilation during moderate hypoxia.