title: The rate-decreasing effects of fentanyl derivatives in pigeons before, during and after chronic morphine treatment.
abstract: Mirfentanil is a fentanyl derivative with non-opioid actions, including non-opioid antinociceptive effects in rhesus monkeys. The current study examined the rate-altering effects of mirfentanil and several other compounds in pigeons to assess: 1) the opioid and non-opioid actions of acutely-administered fentanyl derivatives; and 2) the development of cross-tolerance between each of these compounds and morphine. Seven pigeons responded under a fixed-ratio 20 (FR20) schedule of food delivery. In untreated pigeons, fentanyl, morphine, naltrexone, ketamine and three fentanyl derivatives (mirfentanil, OHM3463 and OHM3295) decreased rates of key pecking in a dose-related manner. Naltrexone (0.1-1.0 mg/kg) attenuated the effects of OHM3463 and not mirfentanil or OHM3295, suggesting non-opioid mediation of the rate-decreasing effects for the latter two fentanyl derivatives. Subjects were treated daily with morphine for 9 weeks, up to a dose of 100 mg/kg per day, during which time the dose-effect curves for morphine, fentanyl and OHM3463 shifted rightward 6-, 10- and 2-fold, respectively, indicating the development of tolerance to morphine and cross-tolerance to fentanyl and OHM3463. Dose-effect curves for ketamine, OHM3295 and mirfentanil were not shifted to the right during morphine treatment, and the dose-effect curve for naltrexone was shifted leftward 180-fold. To the extent that rate-decreasing effects are predictive of antinociceptive effects, these data suggest that some fentanyl derivatives might be useful therapeutics under conditions where tolerance develops to morphine-like opioids.
authors.affiliation: Department of Pharmacology, Louisiana State University Medical Center, New Orleans 70112, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Gauthier
authors.forename: L R
authors.initials: LR
authors.lastname: Gerak
authors.forename: J R
authors.initials: JR
authors.lastname: Bagley
authors.forename: L L
authors.initials: LL
authors.lastname: Brockunier
authors.forename: C P
authors.initials: CP
authors.lastname: France
mesh_terms: D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D010856:Columbidae; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000494:pharmacology; D009020:Morphine / Q000494:pharmacology*; D009271:Naltrexone / Q000494:pharmacology
chemical_list: D000700:Analgesics; C091795:OHM 3295; D009271:Naltrexone; D009020:Morphine; C069209:mirfentanil; D005283:Fentanyl