δ₂ opioid receptor subtype on human vascular endothelium uncouples morphine stimulated nitric oxide release

We demonstrate the presence of both δ and μ opioid receptors on the endothelium of human saphenous vein and internal thoracic artery. Displacement analysis revealed that a variety of opioid peptides were found to be ineffective in displacing specifically bound ³H dihydromorphine and only δ₂ ligands were effective in regard to ³H Ala₂-met₅ enkephalinamide (DAMA), indicating the presence of μ₃ and δ₂ opioid receptor sites, respectively. Confirming the presence of both μ and δ sites we demonstrated positive immunostaining with anti-δ and anti-μ receptor antibodies. Exposure of these vessels to DAMA significantly enhances granulocyte adherence (P<0.01) even in vessels 5 min later exposed to 10^-6 M morphine. Unlike morphine, DAMA did not stimulate nitric oxide from either blood vessel and human granulocytes. Additionally, DAMA preadministered before morphine exposure to the endothelium or granulocytes, inhibited the morphine- stimulated release of NO in a dose-dependent manner. The data indicate that opioid peptides and opiate alkaloids regulate endothelial function in an antagonistic manner thereby influencing the microvascular environment.