Radioligand binding and cDNA homology studies have suggested the existence of opiate receptors distinct from the recently-cloned mu, delta and kappa receptors. XOR1S, a rat brain cDNA whose predicted translation product displays 67-72% homology with those encoded by mu 1, delta 1 and kappa 1 opiate receptor cDNAs, was constructed from two partial cDNAs identified through cDNA homology approaches. A longer XOR1L variant of this cDNA was also identified by polymerase chain reaction studies using genomic DNA and cDNA from brain and peripheral tissues. XOR1 mRNA is most highly expressed in hypothalamus. COS cell expression of both clones confers neither robust binding of opiate ligands nor reproducible opiate inhibition of forskolin-stimulated adenylate cyclase. These studies identify an orphan clone that helps to define features of the opiate receptor gene family, including apparent differential splicing and expression in peripheral tissues.