mu-opioid receptor downregulation contributes to opioid tolerance in vivo

The present study examined the contribution of downregulation of IL-opioid receptors to opioid tolerance in an intact animal model. Mice were implante d subcutaneously with osmotic minipumps that infused etorphine (50-250 mug/ kg/day) for 7 days. Other mice were implanted subcutaneously with a morphin e pellet (25 mg) or a morphine pellet plus an osmotic minipump that infused morphine (5-40 mg/kg/day) for 7 days. Controls were implanted with an iner t placebo pellet. At the end of treatment, pumps and pellets were removed, and saturation binding studies were conducted in whole brain ([H-3]DAMGO) o r morphine and etorphine analgesic ED(50)s were determined (tail-flick). Mo rphine tolerance increased linearly with the infusion dose of morphine (ED5 0 shift at highest infusion dose, 4.76). No significant downregulation of m u -receptors in whole brain was observed at the highest morphine treatment dose. Etorphine produced dose-dependent downregulation of mu -opioid recept or density and tolerance (ED50 shift at highest infusion dose, 6.97). Downr egulation of Cl-receptors only occurred at the higher etorphine infusion do ses ( greater than or equal to 150 mug/kg/day). Unlike morphine tolerance, the magnitude of etorphine tolerance was a nonlinear function of the dose a nd increased markedly at infusion doses that produced downregulation. These results suggest that mu -opioid receptor downregulation contributes to opi oid tolerance in vivo. Therefore, opioid tolerance appears to rely upon bot h "receptor density-dependent" and "receptor density-independent'' mechanis ms. (C) 2001 Elsevier Science Inc. All rights reserved.