Adaptations to prolonged hypoxia include an increase in the expression of proteins that may facilitate survival. One mechanism by which hypoxia increases protein expression involves a change of heme proteins from oxygenated to deoxygenated conformations. In the present study, we tested the hypothesis that treatment of NG108-15 cells with metallic cations, which are known to induce a deoxygenated conformation of heme proteins, would increase delta opioid receptor (DOR) expression. Cells were treated with cobalt and nickel, which induce deoxygenated heme protein conformation, or zinc as a control for 48 h prior to quantifying DOR expression. Cobalt and nickel, but not zinc, significantly increased DOR expression. Heme synthesis inhibitors would block the synthesis of cobalt-substituted heme proteins which are locked in a deoxygenated conformation. The cobalt-induced increase in DOR expression was blocked by the heme synthesis inhibitor, 4,6-dioxoheptanoic acid. These experiments indicate that deoxygenated conformation heme proteins, which are thought to partially mimic hypoxia, increase DOR expression. The increase in DOR expression suggests that the DOR gene may be hypoxia-sensitive. Further, the increase in DOR expression suggests a potential adaptation strategy to hypoxia and may represent one of the first findings of physiological regulation of DOR expression.