In one subclone of PC12 pheochromocytoma cells, PC12h, the levels of delta opioid receptors markedly increase in response to nerve growth factor (NGF). This increase, as assessed by [3H]diprenorphine binding, is found only under specific culture conditions. NGF treatment of PC12h cells also results in the induction of delta opioid receptor (DOR-1) mRNA. The time course for NGF induction of mRNA and protein is similar, although the levels of mRNA increase approximately 5-fold, whereas the levels of receptor increase only 2-fold. Competition studies with selective delta ([D-Pen2,5]-enkephalin, DPDPE), mu ([D-Ala2,N-Me-Phe4,Gly-ol5]- enkephalin, DAMGO) and kappa (trans-[+/-]-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]- benzenacetamide methansulfonate salt, U50,488) opioid agonists to displace [3H]diprenorphine confirm that the delta subtype of opioid receptor is present on PC12h cells. The delta opioid receptor is coupled functionally, as indicated by agonist inhibition of forskolin-stimulated cAMP accumulation in a naloxone-reversible manner. Finally, the delta opioid receptor was cloned from PC12h cells. The sequence was identical with that described previously for the rat clone. The PC12h cell line thus provides a model system in which to study regulation of delta opioid receptors.