mu-Opioid receptor downregulation contributes to opioid tolerance in vivo.
The present study examined the contribution of downregulation of mu-opioid receptors to opioid tolerance in an intact animal model. Mice were implanted subcutaneously with osmotic minipumps that infused etorphine (50-250 microg/kg/day) for 7 days. Other mice were implanted subcutaneously with a morphine 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 inert placebo pellet. At the end of treatment, pumps and pellets were removed, and saturation binding studies were conducted in whole brain ([3H]DAMGO) or morphine and etorphine analgesic ED(50)s were determined (tail-flick). Morphine tolerance increased linearly with the infusion dose of morphine (ED(50) shift at highest infusion dose, 4.76). No significant downregulation of mu-receptors in whole brain was observed at the highest morphine treatment dose. Etorphine produced dose-dependent downregulation of mu-opioid receptor density and tolerance (ED(50) shift at highest infusion dose, 6.97). Downregulation of mu-receptors only occurred at the higher etorphine infusion doses (> or =150 microg/kg/day). Unlike morphine tolerance, the magnitude of etorphine tolerance was a nonlinear function of the dose and increased markedly at infusion doses that produced downregulation. These results suggest that mu-opioid receptor downregulation contributes to opioid tolerance in vivo. Therefore, opioid tolerance appears to rely upon both "receptor density-dependent" and " receptor density-independent" mechanisms.
Stafford
K
K
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Gomes
A B
AB
Shen
J
J
Yoburn
B C
BC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects*; D004343:Drug Implants; D004361:Drug Tolerance; D007202:Indicators and Reagents; D008297:Male; D051379:Mice; D009294:Narcotics / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism
D004343:Drug Implants; D007202:Indicators and Reagents; D009294:Narcotics; D017450:Receptors, Opioid, mu