title: Mu opiate receptors are selectively labelled by [3H]carfentanil in human and rat brain.
abstract: [11C]Carfentanil is a potent opioid agonist currently in use as a specific PET (position emission tomography) scan radioligand for brain mu opioid receptors. In order to investigate the receptor interactions of carfentanil in detail [3H]carfentanil was used as a radioligand for labelling receptors in rat and human brain tissue homogenates. [3H]Carfentanil was found to bind saturably and with high affinity (KD = 0.08 +/- 0.01 nM) to membranes prepared from human cortical (Bmax = 42 +/- 3 fmol/mg) and thalamic (Bmax = 84 +/- 3 fmol/mg) tissues and rat cortex (Bmax = 82 +/- 4 fmol/mg) and diencephalon (Bmax = 105 +/- 5 fmol/mg). Association (1.23 +/- 0.19 X 10(10) Mol-1 X min-1 and dissociation rate (0.19 +/- 0.03 min-1) constants were determined in human cortical tissues; results from studies in rat cortical, and rat diencephalon tissue homogenates produced similar kinetic rate constants. Competition studies with a variety of drugs indicated that [3H]carfentanil interacts primarily with mu opioid receptors in the four tissues studied; the affinities of a series of non-radioactive opioid ligands were essentially identical in the four tissues (correlation coefficients = 0.88-0.93). Naloxone, morphine, DAGO [( D-Ala2-MePhe4-Gly-ol5]enkephalin), DADL [( D-Ala2-D-Leu5]enkephalin) and EKC (ehtylketazocine) potently displaced specific [3H]carfentanil binding with nM potency while the kappa agonist U-69593, the sigma agonists (+)-SKF 10047, (+)-3-PPP [3-hydroxyphenyl)-N-propylpiperidine) and haloperidol and PCP (phencyclidine) were less potent displacing agents. The higher affinities of DAGO and morphine versus DADL for the [3H]carfentanil binding sites indicates that delta opioid receptors are not being labelled.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmacology and Toxicology, Albany Medical College, NY 12208.
authors.forename: M
authors.initials: M
authors.lastname: Titeler
authors.forename: R A
authors.initials: RA
authors.lastname: Lyon
authors.forename: M J
authors.initials: MJ
authors.lastname: Kuhar
authors.forename: J F
authors.initials: JF
authors.lastname: Frost
authors.forename: R F
authors.initials: RF
authors.lastname: Dannals
authors.forename: S
authors.initials: S
authors.lastname: Leonhardt
authors.forename: A
authors.initials: A
authors.lastname: Bullock
authors.forename: L T
authors.initials: LT
authors.lastname: Rydelek
authors.forename: D L
authors.initials: DL
authors.lastname: Price
authors.forename: R G
authors.initials: RG
authors.lastname: Struble
mesh_terms: D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects*; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D004027:Diencephalon / Q000187:drug effects / Q000378:metabolism; D005283:Fentanyl / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006220:Haloperidol / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D009270:Naloxone / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D017450:Receptors, Opioid, mu
chemical_list: D011957:Receptors, Opioid; D017450:Receptors, Opioid, mu; D009270:Naloxone; D006220:Haloperidol; C017114:carfentanil; D005283:Fentanyl