In vivo determination of mu opioid receptor turnover in rhesus monkeys after irreversible blockade with clocinnamox.
In a warm-water tail withdrawal antinociception assay performed at 45, 50 and 55 degrees C in the rhesus monkey, the irreversible opioid antagonist clocinnamox at a dose of 0.1 mg/kg s.c. produced an acute rightward shift of the dose-response curves of the selective mu opioid agonists alfentanil and morphine at all tested temperatures. In addition, clocinnamox depressed the maxima of the dose-response curves for both agonists at 50 and 55 degrees C. Analysis of these data according to Furchgott as modified by Black and Leff showed that clocinnamox acutely decreased mu opioid receptors available for alfentanil by 88%; receptor numbers returned to control levels with a half-life of 6.3 days. Assessment of receptor population changes after clocinnamox administration with either alfentanil or morphine gave essentially identical results: 2 to 4 weeks after clocinnamox, the receptor population not only returned to preclocinnamox levels, but actually showed an overshoot. In contrast, apparent values of alfentanil affinity; its efficacy, e; the theoretically obtainable maximum effect of the mu opioid antinociceptive system, Em; and the stimulus-response transducing factor, n; did not change significantly over time. Alfentanil showed a 29-fold higher affinity than morphine, the respective KA values being 0.84 mg/kg for alfentanil and 24 mg/kg for morphine. The efficacy of alfentanil was always 2- to 3-fold higher than that of morphine for any temperature tested, the efficacies of both mu opioid agonists being higher at lower temperatures.(ABSTRACT TRUNCATED AT 250 WORDS)
Zernig
G
G
Department of Pharmacology, University of Michigan, Ann Arbor.
Butelman
E R
ER
Lewis
J W
JW
Walker
E A
EA
Woods
J H
JH
D015760:Alfentanil / Q000494:pharmacology; D000818:Animals; D002934:Cinnamates / Q000494:pharmacology*; D004347:Drug Interactions; D005260:Female; D007700:Kinetics; D008253:Macaca mulatta; D008297:Male; D009020:Morphine / Q000494:pharmacology; D009022:Morphine Derivatives / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D009619:Nociceptors / Q000187:drug effects; D010147:Pain Measurement / Q000187:drug effects; D011957:Receptors, Opioid / Q000378:metabolism / Q000502:physiology; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013696:Temperature
D002934:Cinnamates; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; C076806:clocinnamox; D015760:Alfentanil; D009020:Morphine