Delta opioid receptors (DORs) and preproenkephalin-A-derived opiate peptides are expressed by mononuclear cells in various lymphoid organs. DOR ligands modulate a variety of immune functions, such as T-cell proliferation, calcium mobilization, and cytokine production. Recently, quiescent T cells were found to express low levels of DOR transcripts, which increased due to the following: cell culture of unstimulated murine splenocytes (depending on cell density); cross-linking the T-cell receptor (TCR) with anti-CD3-epsilon; and a single in vivo exposure to staphylococcal enterotoxin B (SEB). Enhanced expression of DOR mRNA was mediated transcriptionally. Moreover, PMA + ionomycin, which mimic the proliferative signal of anti-CD3, inhibited the expression of DOR mRNA. Using semiquantitative immunofluorescence to detect DORs, SEB was found to increase the fraction of T cells that expressed DOR and to enhance the relative level of DOR expression per T cell. Previous studies have shown that DOR agonists inhibited the anti-CD3-stimulated production of interleukin-2 and T-cell proliferation. Therefore, the enhanced expression of DORs by activated T cells may be capable of downregulating the T-cell activation program.