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°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°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, E(m); and the stimulus-response transducing factor, n; did not change significantly over time. Alfentanil showed a 29-fold higher 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 temperature tested, the efficacies of both mu opioid agonists being higher at lower temperatures. The respective e values were 32 (50°C) and 8 (55°C) for alfentanil and 15 (45°C), 10 (50°C) and 3 (55°C) for morphine. E(m) and n did not differ for the two agonists.