mu-Opioid receptor downregulation contributes to opioid tolerance in vivo

Pharmacol Biochem Behav. May-Jun 2001;69(1-2):233-7. doi: 10.1016/s0091-3057(01)00525-1.


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.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects*
  • Drug Implants
  • Drug Tolerance
  • Indicators and Reagents
  • Male
  • Mice
  • Narcotics / pharmacology*
  • Pain Measurement / drug effects
  • Receptors, Opioid, mu / drug effects*
  • Receptors, Opioid, mu / metabolism


  • Drug Implants
  • Indicators and Reagents
  • Narcotics
  • Receptors, Opioid, mu