Mu-opioid receptor down-regulation and tolerance are not equally dependent upon G-protein signaling

Pharmacol Biochem Behav. 2002 May;72(1-2):273-8. doi: 10.1016/s0091-3057(01)00757-2.


In the present study, the contribution of pertussis toxin (PTX)-sensitive G(i/o)-proteins to opioid tolerance and mu-opioid receptor down-regulation in the mouse were examined. Mice were injected once intracerebroventricularly and intrathecally with PTX (0.1 microg/site). Controls were treated with saline. On the 10th day following PTX treatment, continuous subcutaneous infusion of etorphine (150 or 200 microg/kg/day) or morphine (40 mg/kg/day+25 mg slow-release pellet) was begun. Control mice were implanted with inert placebo pellets. Pumps and pellets were removed 3 days later, and mice were tested for morphine analgesia or mu-opioid receptor density was determined in the whole brain, spinal cord, and midbrain. Both infusion doses of etorphine produced significant tolerance (ED50 shift=approximately 4-6-fold) and down-regulation of mu-opioid receptors (approximately 20-35%). Morphine treatment also produced significant tolerance (ED50 shift= approximately 5-8-fold), but no mu-opioid receptor down-regulation. PTX dramatically reduced the acute potency of morphine and blocked the further development of tolerance by both etorphine and morphine treatments. However, PTX had no effect on etorphine-induced mu-opioid receptor down-regulation in brain, cord, or midbrain. These results suggest that PTX-sensitive G-proteins have a minimal role in agonist-induced mu-opioid receptor density regulation in vivo, but are critical in mediating acute and chronic functional effects of opioids such as analgesia and tolerance.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Down-Regulation / drug effects
  • Down-Regulation / physiology*
  • Drug Tolerance / physiology*
  • GTP-Binding Proteins / metabolism*
  • Male
  • Mesencephalon / drug effects
  • Mesencephalon / metabolism
  • Mice
  • Pertussis Toxin / pharmacology
  • Receptors, Opioid, mu / metabolism*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology*
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism


  • Receptors, Opioid, mu
  • Pertussis Toxin
  • GTP-Binding Proteins