It has previously been shown that endogenous oxytocin (OXT) inhibits the development of acute morphine tolerance. The role of OXT receptors in the central nervous system (CNS) was therefore studied by using a specific OXT receptor antagonist, N-acetyl-(2-O-methyltyrosin)-OXT (ACME-OXT). ACME-OXT (1 pg) was injected into the posterior olfactory nucleus, central amygdaloid nucleus, ventral hippocampus, caudate nucleus or lateral cerebral ventricle. The antagonist facilitated the development of tolerance to morphine when injected into the posterior olfactory nucleus, central amygdaloid nucleus or ventral hippocampal areas, which are known to contain OXT binding sites. When administered into the caudate nucleus (with no OXT binding sites) or the lateral cerebral ventricle, it had no effect on morphine tolerance. Our results suggest that the limbic forebrain OXT receptors play an important inhibitory role in adaptive responses to morphine.