Decrease in mu-opioid receptor binding capacity in rat brain after chronic PL017 treatment.
In previous studies, we have demonstrated that chronic treatment of rats with either etorphine or D-Ala2, D-Leu5-enkephalin (DADLE) resulted in the reduction of opioid receptor binding activities during the course of tolerance development. In both cases, mu-opioid receptor binding capacity was attenuated together with the delta-opioid receptor binding capacity. Because both etorphine and DADLE are relatively non-specific opioid ligands, interacting with both mu and delta receptors, these studies could not determine whether down-regulation of a specific receptor type is possible. Therefore, in the current studies, animals were rendered tolerant to the mu-opioid receptor-selective ligand PL017 and the receptor binding capacity was measured afterwards. Treating Sprague-Dawley rats with increasing doses of PL017 (2.5-20 micrograms/kg) i.c.v. for 5 days resulted in a 30- to 40-fold increase in the AD50 of the peptide to elicit the antinociceptive response and about 14-fold increase in the ED50 of the peptide to elicit the catatonic effect. When mu- and delta-binding was determined using [3H]diprenorphine in the presence of morphiceptin or DPDPE respectively, a significant decrease (20-30%) in the mu-opioid receptor binding but not in delta-opioid receptor binding was observed in all the brain areas tested after 5 days of PL017 treatment. Scatchard analysis of the [3H]DAMGO saturation binding data revealed a decrease in Bmax values and no change in the Kd values. Hence, mu-opioid receptors can be specifically regulated by ligand in the brain as delta-receptors are in neuroblastoma x glioma NG 108-15 cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Tao
P L
PL
Department of Pharmacology, National Defense Medical Center, Taipei, Taiwan.
Lee
H Y
HY
Chang
L R
LR
Loh
H H
HH
D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002389:Catatonia / Q000139:chemically induced; D004174:Diprenorphine / Q000378:metabolism; D004361:Drug Tolerance / Q000502:physiology; D004723:Endorphins / Q000494:pharmacology*; D016308:Enkephalin, Leucine-2-Alanine / Q000494:pharmacology; D008297:Male; D008566:Membranes / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000187:drug effects*; D017450:Receptors, Opioid, mu; D014316:Tritium
D004723:Endorphins; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D014316:Tritium; D004174:Diprenorphine; D016308:Enkephalin, Leucine-2-Alanine; C044708:morphiceptin, N-Me-Phe(3)-