In vivo binding of benzomorphans to mu, delta and kappa opioid receptors: comparison with urine output in the rat.

In vivo binding affinities of three benzomorphans, Win 44,441-3, bremazocine and MR 2266, were determined at the mu, delta and kappa types of opioid binding sites in rat brain, using an ex vivo labeling technique. The receptor occupancy of the benzomorphans and of previously tested diprenorphine were compared with their activities in increasing urine output (agonist ED50: bremazocine) or inhibiting bremazocine-induced diuresis (antagonist ID50: Win 44,441-3, MR 2266 and diprenorphine). The agonist, bremazocine, bound (in order of decreasing affinity) to the kappa approximately equal to mu greater than delta binding sites, and it's pharmacological effects appeared in the dosage range of kappa and mu binding. In order to positively identify which receptor type is responsible, the potency of the three antagonists to block the effects of bremazocine were compared to their ability to occupy the individual sites in vivo. A fractional occupancy of 0.5 would be expected at the ID50 if one assumes a linear relationship between receptor occupancy by the antagonist and the antagonistic effect. Such a linear relationship was observed for the three antagonists only at the kappa site, whereas variable occupancies were observed at the mu and delta sites. These results support the previously proposed hypothesis that kappa receptors mediate the effects of benzomorphan opioid drugs on urine flow.