Decrease in delta and mu opioid receptor binding capacity in rat brain after chronic etorphine treatment

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The modulatory effect of continued activation of opiate receptors with agonist on the receptor level was examined in current studies. Rats were rendered tolerant to etorphine by s.c. implantation of osmotic minipumps containing 3 mg/ml of etorphine for up to 7 days. During this period, there were a time-dependent increase in the AD50 values of etorphine to inhibit the tail-flick response and an increase in naloxone-precipitated withdrawal signs. When these animals and others were sacrificed and the opiate receptor binding properties were examined, it could be demonstrated that there was also a time-dependent decrease in the amount of [3H]diprenorphine specifically bound, with maximal attenuation reached 3 days after implantation. There was no alteration in alpha2 adrenergic receptor binding. This observed decrease in [3H]diprenorphine binding was not due to the presence of nonwashed etorphine in the membrane, for acute administration of the same dose of etorphine before sacrificing did not produce an attenuation of the opiate receptor binding. Further examination of opiate receptor binding in the brain regions of cortex, midbrain and striatum revealed the greatest decrease in the amount of [3H]diprenorphine bound in striatal region after chronic etorphine treatment, a 68% decrease. When the relative decrease in mu and delta opioid receptor binding was determined by carrying out [3H]-D-Ala2,D-Leu5-enkephalin binding in the presence of 1 μM morphiceptin, it was observed that, 3 days after etorphine treatment, there was a decrease in mu opioid receptor binding, with minimal change in delta opioid receptor binding in both brain regions of striatum and midbrain. Only in cortex was a decrease in binding of both receptor subtypes observed. This decrease in opiate receptor binding after chronic etorphine treatment was due to the decrease in B(max) values and not in the K(d) values, as in the case of nonwashed membrane containing etorphine. Also, an apparent increase in the affinity of [3H] diprenorphine was observed during chronic opiate treatment. These observed alterations in opiate receptor binding were opioid dependent, for chronic treatment of animals with either morphine or naloxone produced an increase rather than a decrease in receptor binding. Chronic etorphine treatment did not alter the maximal inhibitory level of opiate regulation of adenylate cyclase in the striatum, but a 2.2-fold increase in D-Ala2,D-Leu5-enkephalin ID50 value was observed after 5 days of etorphine treatment. Therefore, in addition to the observed delta opioid receptor down-regulation in clonal cell lines, chronic activation of the opiate receptor in brain with etorphine produced an apparent down-regulation of both the mu and delta opioid receptors.

Original languageEnglish (US)
Pages (from-to)809-816
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Jan 1 1987


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