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 ant agonist clocinnamox at a dose of 0.1 mg/kg s.c. produced an acute righ tward shift of the dose-response curves of the selective mu opioid ago nists 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 acutel y decreased mu opioid receptors available for alfentanil by 88%; recep tor numbers returned to control levels with a half-life of 6.3 days. A ssessment of receptor population changes after clocinnamox administrat ion with either alfentanil or morphine gave essentially identical resu lts: 2 to 4 weeks after clocinnamox, the receptor population not only returned to preclocinnamox levels, but actually showed an overshoot. I n contrast, apparent values of alfentanil affinity; its efficacy, e; t he theoretically obtainable maximum effect of the mu opioid antinocice ptive system, E(m); and the stimulus-response transducing factor, n; d id not change significantly over time. Alfentanil showed a 29-fold hig her affinity than morphine, the respective K-A 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 temperatu re tested, the efficacies of both mu opioid agonists being higher at l ower temperatures. The respective e values were 32 (50 degrees C) and 8 (55 degrees C) for alfentanil and 15 (45 degrees C), 10 (50 degrees C) and 3 (55 degrees C) for morphine. E(m) and n did not differ for th e two agonists.