In vivo labeling of delta opioid receptors in mouse brain by [3H]benzylidenenaltrexone, a ligand selective for the delta1 subtype

John R. Lever, Marigo Stathis, Chris M. Kinter, Ursula Scheffel

Research output: Contribution to journalArticle

Abstract

(E)-7-Benzylidenenaltrexone (BNTX) is a selective ligand for the putative deltai (δ1) opioid receptor. To explore the feasibility of labeling δ1 sites in vivo, we determined the cerebral distribution of radioactivity after systemic administration of [3H]BNTX to CD1 mice. Uptake was highest in striatum and lowest in cerebellum throughout the 4 hr time course. Specific radioligand binding, approximated as the difference in radioactivity concentrations between striatum and cerebellum, peaked at 0.32 percent injected dose/g at 30 min and comprised a modest 23% of total striatal radioactivity. For seven brain regions, radioactivity concentrations correlated with δ site densities known from prior in vitro studies (rs = 0.79, p = 0.03), and also with the uptake of N1′-([11C]methyl)naltrindole in vivo (rs = 0.78, p = 0.04) in mice. Specific binding in striatum, olfactory tubercles and cortical regions was saturable by BNTX, and was inhibited stereoselectively by the optical isomers of naloxone. Naltrindole and naltriben (NTB), δ antagonists, blocked 65 -99% of [3H]BNTX specific binding at a dosage of 5.0 μmol/kg. Similar doses of the μ antagonist cyprodime, or the K agonist U50,488H, did not inhibit binding. Adjusted for the four-fold greater brain penetration of NTB relative to BNTX, dose-response studies suggested that δ1 selective BNTX (ED50 = 1.51 μmol/kg) was 50% more potent than δ2 selective NTB (ED50 = 0.56 μmol/kg) in blocking specific [3H]BNTX binding in striatum. In CXBK mice, a strain with functional δ1 but not δ2 receptors in antinociceptive assays, radioligand uptake and distribution proved similar to that in CD1 mice. In sum, [3H]BNTX labels murine δ opioid receptors in vivo with a low extent of specific binding. The data is consistent with, but not conclusive for, selective labeling of the δ1 subtype.

Original languageEnglish (US)
JournalLife Sciences
Volume58
Issue number21
DOIs
StatePublished - Apr 19 1996

Fingerprint

delta Opioid Receptor
Labeling
Brain
Ligands
naltrindole
Radioactivity
Opioid Receptors
Cerebellum
Corpus Striatum
Radioligand Assay
7-benzylidenenaltrexone
Naloxone
Isomers
Labels
Assays

Keywords

  • Benzylidenenaltrexone
  • Delta opioid receptors
  • Naltriben

ASJC Scopus subject areas

  • Pharmacology

Cite this

In vivo labeling of delta opioid receptors in mouse brain by [3H]benzylidenenaltrexone, a ligand selective for the delta1 subtype. / Lever, John R.; Stathis, Marigo; Kinter, Chris M.; Scheffel, Ursula.

In: Life Sciences, Vol. 58, No. 21, 19.04.1996.

Research output: Contribution to journalArticle

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title = "In vivo labeling of delta opioid receptors in mouse brain by [3H]benzylidenenaltrexone, a ligand selective for the delta1 subtype",
abstract = "(E)-7-Benzylidenenaltrexone (BNTX) is a selective ligand for the putative deltai (δ1) opioid receptor. To explore the feasibility of labeling δ1 sites in vivo, we determined the cerebral distribution of radioactivity after systemic administration of [3H]BNTX to CD1 mice. Uptake was highest in striatum and lowest in cerebellum throughout the 4 hr time course. Specific radioligand binding, approximated as the difference in radioactivity concentrations between striatum and cerebellum, peaked at 0.32 percent injected dose/g at 30 min and comprised a modest 23{\%} of total striatal radioactivity. For seven brain regions, radioactivity concentrations correlated with δ site densities known from prior in vitro studies (rs = 0.79, p = 0.03), and also with the uptake of N1′-([11C]methyl)naltrindole in vivo (rs = 0.78, p = 0.04) in mice. Specific binding in striatum, olfactory tubercles and cortical regions was saturable by BNTX, and was inhibited stereoselectively by the optical isomers of naloxone. Naltrindole and naltriben (NTB), δ antagonists, blocked 65 -99{\%} of [3H]BNTX specific binding at a dosage of 5.0 μmol/kg. Similar doses of the μ antagonist cyprodime, or the K agonist U50,488H, did not inhibit binding. Adjusted for the four-fold greater brain penetration of NTB relative to BNTX, dose-response studies suggested that δ1 selective BNTX (ED50 = 1.51 μmol/kg) was 50{\%} more potent than δ2 selective NTB (ED50 = 0.56 μmol/kg) in blocking specific [3H]BNTX binding in striatum. In CXBK mice, a strain with functional δ1 but not δ2 receptors in antinociceptive assays, radioligand uptake and distribution proved similar to that in CD1 mice. In sum, [3H]BNTX labels murine δ opioid receptors in vivo with a low extent of specific binding. The data is consistent with, but not conclusive for, selective labeling of the δ1 subtype.",
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N2 - (E)-7-Benzylidenenaltrexone (BNTX) is a selective ligand for the putative deltai (δ1) opioid receptor. To explore the feasibility of labeling δ1 sites in vivo, we determined the cerebral distribution of radioactivity after systemic administration of [3H]BNTX to CD1 mice. Uptake was highest in striatum and lowest in cerebellum throughout the 4 hr time course. Specific radioligand binding, approximated as the difference in radioactivity concentrations between striatum and cerebellum, peaked at 0.32 percent injected dose/g at 30 min and comprised a modest 23% of total striatal radioactivity. For seven brain regions, radioactivity concentrations correlated with δ site densities known from prior in vitro studies (rs = 0.79, p = 0.03), and also with the uptake of N1′-([11C]methyl)naltrindole in vivo (rs = 0.78, p = 0.04) in mice. Specific binding in striatum, olfactory tubercles and cortical regions was saturable by BNTX, and was inhibited stereoselectively by the optical isomers of naloxone. Naltrindole and naltriben (NTB), δ antagonists, blocked 65 -99% of [3H]BNTX specific binding at a dosage of 5.0 μmol/kg. Similar doses of the μ antagonist cyprodime, or the K agonist U50,488H, did not inhibit binding. Adjusted for the four-fold greater brain penetration of NTB relative to BNTX, dose-response studies suggested that δ1 selective BNTX (ED50 = 1.51 μmol/kg) was 50% more potent than δ2 selective NTB (ED50 = 0.56 μmol/kg) in blocking specific [3H]BNTX binding in striatum. In CXBK mice, a strain with functional δ1 but not δ2 receptors in antinociceptive assays, radioligand uptake and distribution proved similar to that in CD1 mice. In sum, [3H]BNTX labels murine δ opioid receptors in vivo with a low extent of specific binding. The data is consistent with, but not conclusive for, selective labeling of the δ1 subtype.

AB - (E)-7-Benzylidenenaltrexone (BNTX) is a selective ligand for the putative deltai (δ1) opioid receptor. To explore the feasibility of labeling δ1 sites in vivo, we determined the cerebral distribution of radioactivity after systemic administration of [3H]BNTX to CD1 mice. Uptake was highest in striatum and lowest in cerebellum throughout the 4 hr time course. Specific radioligand binding, approximated as the difference in radioactivity concentrations between striatum and cerebellum, peaked at 0.32 percent injected dose/g at 30 min and comprised a modest 23% of total striatal radioactivity. For seven brain regions, radioactivity concentrations correlated with δ site densities known from prior in vitro studies (rs = 0.79, p = 0.03), and also with the uptake of N1′-([11C]methyl)naltrindole in vivo (rs = 0.78, p = 0.04) in mice. Specific binding in striatum, olfactory tubercles and cortical regions was saturable by BNTX, and was inhibited stereoselectively by the optical isomers of naloxone. Naltrindole and naltriben (NTB), δ antagonists, blocked 65 -99% of [3H]BNTX specific binding at a dosage of 5.0 μmol/kg. Similar doses of the μ antagonist cyprodime, or the K agonist U50,488H, did not inhibit binding. Adjusted for the four-fold greater brain penetration of NTB relative to BNTX, dose-response studies suggested that δ1 selective BNTX (ED50 = 1.51 μmol/kg) was 50% more potent than δ2 selective NTB (ED50 = 0.56 μmol/kg) in blocking specific [3H]BNTX binding in striatum. In CXBK mice, a strain with functional δ1 but not δ2 receptors in antinociceptive assays, radioligand uptake and distribution proved similar to that in CD1 mice. In sum, [3H]BNTX labels murine δ opioid receptors in vivo with a low extent of specific binding. The data is consistent with, but not conclusive for, selective labeling of the δ1 subtype.

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