Opioid receptor expression and function traditionally have been studied in neuronal cells and recently in mature lymphoid cells; however, little is known about their possible functions in hematopoietic stem cells (CD34(+) cells). We studied the expression of the mu receptor on CD34(+) cells and assessed the signal transduction cascade it induces.Mu-receptor expression on cord blood (CB) and peripheral blood (PB) CD34(+) cells was studied by microarrays, immunostaining, and fluorescence-activated cell sorting analysis. Signal transduction by the mu receptor was studied through Western blots and kinase assay of enkephalin-activated CB CD34(+) cells. Apoptotic, differentiation, and proliferation responses following mu-receptor activatioSn were studied by annexin V assay and inverted microscopy.A prominent difference in gene expression, in favor of CB compared to PB CD34(+) cells, was observed in the mu-receptor gene. This receptor was mainly expressed on the CB CD34(+)CD38(-) subpopulation. A MAP kinase signal transduction cascade was shown to be induced through activation of this receptor by enkephalin or morphine.We showed for the first time that the mu receptor is expressed on immature CB stem cells and that its activation by enkephalin or morphine induces a MAP kinase signal transduction cascade. Because the MAP kinase cascade is known to elicit proliferation and differentiation responses, these findings suggest a possible role of endogenous enkephalins in hematopoietic stem cell proliferation and differentiation and may lead to therapeutic applications of opiates in CB stem cell expansion and neuronal differentiation.