We screened a PHA (phytohemagglutinin)-activated human lymphocyte cDNA library for clones with homology to the recently cloned brain opioid receptors. A cDNA clone, AT7-5EU, was isolated which encodes the opioid 'orphan' receptor, a molecule with very high homology to the opioid receptor gene family, but which has not been shown to bind opioids or any other known compounds. The protein coding region of AT7-5EU has complete homology with a reported opioid 'orphan' clone isolated from human brain, but the 5' untranslated regions of AT7-5EU and the human brain clones are divergent, suggesting mechanisms for tissue-specific expression of this receptor. Northern analysis of AT7-5EU mRNA demonstrates the expression of this message in human lymphocytic cell lines of both B-and T-cell lineages. Furthermore, analysis of mRNA from human peripheral blood lymphocytes demonstrates that activation of the lymphocytes with PHA results in at least a 10-fold induction of the AT7-5EU message. These results suggest that the opioid 'orphan' receptor may have an important immunological function in addition to its function in the nervous system.