Electrophoretic administration of the mu selective opioid agonist [D-Ala2, NMe-Phe4, Gly-ol]-Enkephalin (DAMGO) in the dentate gyrus of the hippocampus acutely produces a marked increase in the responsiveness of dentate granule cells to perforant path stimulation. This can be measured by an increase in the primary population spike (PS) amplitude and by disinhibition in the paired-pulse (PP) paradigm. Concomitantly, the spontaneous single unit activity of interneurons is usually inhibited. We have observed that after prolonged (usually 10-20 min) local (electrophoretic) administration of DAMGO, a second, late effect is noted, suggesting acute desensitization. There is a loss of the disinhibition seen in the PP paradigm while the primary PS shows only some increased variability in response to stimulation. Furthermore, in a time course parallel to the loss of disinhibition, single cell activity initially inhibited by DAMGO appears to lose its responsiveness. Pretreatment with kappa or delta opioid agonists, or with GABA agonists and antagonists, does not affect the development of this desensitization suggesting selective involvement of the mu receptor. We further propose a regional specificity within the hippocampus since we are unable to detect evidence of desensitization to opioid in CA1 using the same techniques.