A variety of neuropeptide receptors have been detected in human lung cancer. They are thought to play a role in autocrine/paracrine regulation of cell growth, and may be clinically useful as diagnostic, prognostic or therapeutic targets. The current study characterizes the molecular structure of the delta opioid receptor and its gene expression level in lung cancer cell lines relative to normal human lung using a sensitive RT-PCR approach. The goals of this investigation were a) to define the correlation between receptor binding and gene expression in lung cancer cell lines, and b) to determine the cDNA sequence integrity of this receptor in comparison to the receptor recently found in human brain. Five small cell lung cancer (SCLC) cell lines revealed size-matched RT-PCR products which strongly hybridized to the human brain delta opioid receptor probe. One of three non-small cell lung cancer (NSCLC) cell lines (NCI-H23), known to be negative by binding analysis, demonstrated low level expression. No gene expression was found in normal human lung. RT-PCR products from two SCLC cell lines (SCLC-22H and 16HC) as well as the low level expressing NSCLC cell line (NCI-23) were subjected to bidirectional DNA sequence analysis and the receptor ends were resolved using a 3'-end RACE and 5'-end gene-specific approach. The isolated cDNA sequences proved to be identical to the published human brain delta opioid receptor sequence. These data show that lung cancers with neuroendocrine features express human brain delta opioid receptors in contrast to normal lung, and that the delta opioid receptor mRNA in lung cancer is not mutated. This unique feature of lung cancer may be exploitable for diagnostic, prognostic, and therapeutic strategies.