title: Magnitude of tolerance to fentanyl is independent of mu-opioid receptor density.
abstract: The effect of a mu-opioid receptor irreversible antagonist on the development of tolerance to fentanyl was determined in mice. Mice were injected with saline or clocinnamox (3.2 mg/kg, i.p.) and 4 h later mice implanted s.c. with a placebo pellet or an osmotic minipump that infused fentanyl (0.165 mg/kg per day) for 3 days. Fentanyl pumps and placebo pellets were removed on the third day following implantation and 4 h later mu-opioid receptor saturation binding studies in whole brain ([3H][D-Ala2,MePhe4,Gly-ol5]enkephalin: DAMGO) or fentanyl analgesic dose-response studies (tailflick assay) were conducted. Fentanyl infusions and clocinnamox both significantly reduced the potency of fentanyl by 2.8- and 2.4-fold, respectively. When fentanyl and clocinnamox were administered together, a significant 5.0-fold reduction in fentanyl potency relative to the saline-placebo group was observed, which represents an additive effect of clocinnamox and fentanyl. The ED50 of fentanyl in clocinnamox-treated mice was shifted 2.1-fold by fentanyl infusion relative to the clocinnamox-placebo group. This is comparable to the 2.8-fold shift in the ED50 produced by fentanyl infusion in saline-treated mice. In binding studies, fentanyl produced a small (-9%) reduction in Bmax, while clocinnamox significantly reduced (-41%) mu-opioid receptor density without altering affinity (Kd). In the clocinnamox-fentanyl group, there was a 50% reduction in Bmax, which is similar to the additive effect observed in analgesia studies. These data indicate that changes in mu-opioid receptor density prior to the development of tolerance to fentanyl do not impact on the magnitude of tolerance.
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy and Allied Health Professions, St. John's University, Queens, NY 11439, USA.
authors.forename: K W
authors.initials: KW
authors.lastname: Chan
authors.forename: A
authors.initials: A
authors.lastname: Duttory
authors.forename: B C
authors.initials: BC
authors.lastname: Yoburn
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D004343:Drug Implants; D004361:Drug Tolerance; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D004745:Enkephalins / Q000494:pharmacology; D005283:Fentanyl / Q000008:administration & dosage / Q000494:pharmacology*; D007700:Kinetics; D008297:Male; D051379:Mice; D009022:Morphine Derivatives / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D011930:Reaction Time / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000502:physiology*
chemical_list: D000700:Analgesics; D002934:Cinnamates; D004343:Drug Implants; D004745:Enkephalins; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D009294:Narcotics; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; C076806:clocinnamox; D005283:Fentanyl