MORPHINE-INDUCED CONFORMATIONAL-CHANGES IN HUMAN MONOCYTES, GRANULOCYTES, AND ENDOTHELIAL-CELLS AND IN INVERTEBRATE IMMUNOCYTES AND MICROGLIA ARE MEDIATED BY NITRIC-OXIDE

We evaluated the contribution of nitric oxide (NO) to morphine-induced rounding of spontaneously activated (mobile) ameboid human monocytes, granulocytes, or arterial endothelial cells and invertebrate immunocy tes and microglia. Morphine induced significant rounding and inactivat ion of ameboid cells within 20 min except for arterial endothelial cel ls, which became rounded 24 h after morphine exposure. The effects of morphine on cell conformation were blocked in the presence of N-nitro- L-arginine, a nitric oxide synthase inhibitor, Treatment of cells with the NO donor, sodium nitroprusside, induced cell rounding similar to that observed following morphine exposure, suggesting that NO release may mediate morphine-induced changes in cell conformation, The contrib ution of NO release to morphine-induced cell rounding was determined b y direct evaluation of NO concentration in real-time using a NO-specif ic amperometric probe. Significant increases in NO concentration were observed 2 min after morphine stimulation, whereas morphine-induced NO release was markedly impaired by pretreatment with N-nitro-L-arginine or the opiate alkaloid antagonist, naloxone, In contrast, opioid pept ides failed to induce NO release, consistent with our previous observa tions that demonstrated the failure of opioid peptides to promote cell rounding. Taken together, these data suggest that morphine-induced NO release may be mediated by activation of the opiate alkaloid-selectiv e, opioid peptide-insensitive mu(3) receptor, and that functional coup ling of morphine to NO production has been conserved during evolution and may modulate cellular activation.