Down regulation of opiate receptor in rat brain after chronic etorphine treatment

Osmotic minipumps implantation subcutaneously produced tolerance to etorphine in rats, as demonstrated by the time dependent increase of the etorphine AD₅₀ values. Furthermore, there was a time dependent decrease in the opiate receptor binding sites associated with chronic etorphine treatment. Obviously, one could argue that the observed decrease was due to the unwashed etorphine. However, this is unlikely because our washing procedure could remove all the etorphine specifically bound to the membrane. Moreover, Scatchard analysis indicated that the decrease in ³H-diprenorphine binding was due to a decrease in Bmax values. If the decrease in opiate binding was due to the presence of non-washed etorphine, decrease in the Kd values should be observed. This was indeed the case when the etorphine in the acute opiate treated animals was not removed. Hence it can be concluded that chronic opiate treatment elicited a receptor down regulation in the brain. Which opiate receptor subtypes is preferentially down regulated is unknown. Apparently, the degree of receptor down-regulation did not correlate with the degree of tolerance. For the AD₅₀ value of etorphine continued to increase after 3 days, but the percentage of binding decrease had reached its maximum after 3 days. The pharmacological significance of opiate receptor down regulation remained to be elucidated.