To directly compare the regulation of the cloned κ and μ opioid receptor, we expressed them in the same cells, the mouse anterior pituitary cell line AtT-20. The coupling of an endogenous somatostatin receptor to adenylyl cyclase and an inward rectifier K + current has been well characterized in these cells, enabling us to do parallel studies comparing the regulation of both the κ and the μ receptor to this somatostatin receptor. We show that the κ receptor readily uncoupled from the K + current and from adenylyl cyclase after a 1 h pretreatment with agonist, as indicated by the loss in the ability of the agonist to induce a functional response. The desensitization of the κ receptor was homologous, as the ability of somatostatin to mediate inhibition of adenylyl cyclase or potentiation of the K + current was not altered by κ receptor desensitization. The μ receptor uncoupled from the K + current but not adenylyl cyclase after a 1 h pretreatment with agonist. Somatostatin was no longer able to potentiate the K + current after μ receptor desensitization, thus this desensitization was heterologous. Interestingly, pretreatment with a somatostatin agonist caused uncoupling of the μ receptor but not the κ receptor from the K + current. These results show that in the same cell line, after a 1 h pretreatment with agonist, the κ receptor displays homologous regulation, whereas the μ receptor undergoes only a heterologous form of desensitization. μ Receptor desensitization may lead to the alterations of diverse downstream events, whereas κ receptor regulation apparently occurs at the level of the receptor itself. Broad alterations of non-opioid systems by the μ receptor could be relevant to the addictive properties of μ agonists. Comparison of κ and μ receptor regulation may help define the properties of the μ receptor which are important in the development of addiction, tolerance, and withdrawal to opioid drugs. These are the first studies to directly compare the coupling of the κ and μ receptors to two different effectors in the same mammalian expression system.