Down-regulation of delta but not mu opioid receptors in the hippocampal slice associated with loss of physiological response.

In rat hippocampal slices, opioids potentiate the synaptic activation of pyramidal neurons as revealed by the shift to the left in the input-output curve constructed by plotting the population spike as a function of the field EPSP. The peak effect was obtained within 12-25 min with D-Ala2,D-Leu5-enkephalin (DADLE), morphiceptin and morphine. However, the effect of both peptides declined during constant superfusion. About 60% peak effect was lost after 1 hr superfusion with morphiceptin or after 4 hr with DADLE. In contrast, the effect of morphine gradually increased over a 4 hr incubation. Following superfusion of the slices for 4 hr in DADLE or morphine, or 1.5 hr in morphiceptin, the membrane particulate fractions were prepared from the homogenate of slices. Opiate receptor binding activities were measured with 125I-DADLE (delta-receptors) and 125I-FK 33824 (mu-receptors). A significant reduction in delta- but not mu-receptor binding was detected in slices treated with DADLE. This seems to correlate to the development of desensitization to DADLE. Neither mu-receptor nor delta-receptor binding activity was altered by the superfusion of morphine or morphiceptin despite the development of desensitization to morphiceptin. These data suggest that there are differences in the regulation of mu- and delta-receptors in hippocampus. The down-regulation of delta-receptors may result in desensitization to delta-agonists and a different mechanism may be responsible for desensitization to mu-agonists.