Mu-opioid receptor down-regulation and tolerance are not equally dependent upon G-protein signaling.
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.
Gomes
Benedict A
BA
Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, 8000 Utopia Parkway, Queens, NY 11439, USA.
Shen
Ji
J
Stafford
Kristi
K
Patel
Minesh
M
Yoburn
Byron C
BC
D000818:Animals; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D004361:Drug Tolerance / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D037342:Pertussis Toxin / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism
D017450:Receptors, Opioid, mu; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins