Control of opiate receptor number in vivo: simultaneous kappa-receptor down-regulation and mu-receptor up-regulation following chronic agonist/antagonist treatment.

While it is well established that opiate receptors up-regulate following chronic antagonist treatment in vivo, possible down-regulation following chronic agonist treatment remains controversial. In this study, rats received a continuous seven-day infusion of bremazocine, an opioid drug suggested to be a potent agonist at kappa receptors and an antagonist at mu and delta receptors. Opiate receptor binding was assessed in both cryostat sections and homogenates of rat brain, under conditions selective for mu, delta and kappa sites. Data from both sections and homogenates showed an increase in the capacity of mu binding sites following chronic bremazocine treatment, suggesting that up-regulation of mu receptors had occurred, and that residual ligand from the in vivo treatment had largely been removed. A significant decrease in kappa binding was observed in sections, and experiments using homogenates demonstrated a dramatic loss of high-affinity kappa binding, with an increase in low-affinity binding. There was no apparent alteration in binding to delta receptors. No significant changes were observed following acute injection of bremazocine. Quantitative light-microscopic autoradiography confirmed the results of the binding experiments, and showed that the magnitude of these effects varied between different brain regions. No decrease in kappa binding was seen following chronic administration of the partial kappa agonist nalorphine, indicating that high agonist intrinsic activity is necessary for down-regulation to occur. In addition, chronic co-administration of bremazocine with the partial agonist/antagonist diprenorphine did not cause a significant decrease in kappa binding, implying that diprenorphine can antagonize the down-regulatory effect. These results provide evidence that bremazocine possesses different degrees of intrinsic activity at mu, delta and kappa receptors. They demonstrate that, at least in the case of kappa sites, opiate receptors do show down-regulation following chronic agonist treatment in vivo.