PRESENCE OF THE MU(3) OPIATE RECEPTOR IN ENDOTHELIAL-CELLS - COUPLINGTO NITRIC-OXIDE PRODUCTION AND VASODILATION

Initial confinement of opiate receptors to the nervous system has rece ntly been broadened to several other cell types. Based on the well est ablished hypotensive effect of morphine, we hypothesized that endothel ial cells may represent a target for this opiate substance. Endothelia l cells (human arterial and rat microvascular) contain a high affinity , saturable opiate binding site presumed to mediate the morphine effec ts that is stereoselectively and characteristically antagonized by nal oxone. This opiate alkaloid-specific binding site is insensitive to op ioid peptides. It is, therefore, considered to be the same subtype of opiate receptor (designated mu(3)) used in the mediation of morphine i n other cell types exhibiting the same binding profile. Experiments wi th endothelial cultures and the aortic ring of rats cultured in vitro demonstrate that morphine exerts direct modulatory control over the ac tivities of endothelial cells, which leads to vasodilation. It induces the production of nitric oxide, a process that is sensitive to naloxo ne antagonism and nitric oxide synthase inhibition. In contrast with t hat of opiates, the administration of opioid peptides does not induce nitric oxide production by endothelial cells. In conclusion, the data presented above reveal a novel site of morphine action, endothelial ce lls, where a mu(3) receptor is coupled to nitric oxide release and vas odilation.