Human granulocytes contain an opiate alkaloid-selective receptor mediating inhibition of cytokine-lnduced activation and chemotaxis

Human peripheral blood granulocytes previously were found to contain opioid δ₂-receptors mediating stimulation by opioid peptides of chemotaxis. Studies presented in this work indicate that granulocytes also contain opiate alkaloid-selective, opioid peptide-insensitive receptors mediating inhibition by morphine and other opiates of cyctokine-induced activation and chemotaxis. Binding studies with [³H]morphine and [³H]diprenorphine ([³H]DPN) indicated the presence of receptor sites, at considerable density with affinities and selectivity for opiates comparable with those of the μ₃-receptor of human peripheral blood monocytes (macrophages). The influence of the guanosine 5′-triphosphate (GTP) analogue GppNHp on binding indicated that the granulocyte receptor was linked to a G protein. Morphine but not opioid peptides interfered with activation and/or chemotaxis of the granulocytes induced by TNF-α, IL-1α, IL-8, and FMLP (chemotactic peptide). These effects of morphine were blocked by the antagonist naloxone. Levorphanol inhibited TNF-α-induced activation, and also potentiated the inhibition by morphine. Furthermore, in binding assays, levorphanol enhanced the affinity of the receptor for morphine. Dextrorphan had no effect on activation or chemotaxis, and it also had no effect on binding, indicative of stereoselectivity for the effects of levorphanol. It is concluded that human granulocytes contain opiate alkaloid-selective μ₃-receptors that mediate inhibitory effects of morphine on cellular activation by cytokines.