Characterization and autoradiographic visualization of (+)-[3H]SKF10,047 binding in rat and mouse brain: Further evidence for phencyclidine/'sigma opiate' receptor commonality

R. Sircar, R. Nichtenhauser, J. R. Ieni, S. R. Zukin

Research output: Contribution to journalArticle

Abstract

The binding specificity of (+)-[3H]N-allylnormetazocine, the dextrorotatory isomer of the prototypical sigma opiate SKF10,047, was determined in rat and mouse brain and the neuroanatomical distribution of its binding sites elucidated by quantitative autoradiography in sections of rat brain. Computer-assisted Scatchard analysis revealed an apparent two-site fit of the binding data in both species and in all rat brain regions examined. In whole rat brain, the K(d) values were 3.6 and 153 nM and the maximum binding values were 40 fmol and 1.6 pmol/mg of protein for the apparent high- and low-affinity binding sites, respectively. (+)-SKF-10,047, haloperidol and pentazocine were among the most potent inhibitors of 7 nM (+)-[3H]SKF10,047 binding to the higher affinity sites; rank orders of ligand potencies at these sites differ sharply from those that have been reported for the [3H]phencyclidine (PCP) site, or for eliciting PCP-like or SKF10,047-like behaviors. By contrast, rank orders of potency of sigma opioids, PCP derivatives and dioxolanes for displacement of 100 nM (+)-3H]SKF10,047 from the more numerous lower affinity sites in the presence of 100 nM haloperidol agreed closely with their potencies in the [3H]PCP binding assay as well as their potencies in exerting PCP- or SKF10,047-like behavioral effects. In order to compare directly the anatomical localizations of PCP and (+)-SKF10,047 binding sites, quantitative light microscopy autoradiography utilizing tritium-labeled PCP and (+)-SKF10,047 was carried out in rat brain sections. (+)-[3H]SKF10,047 binding was observed to follow the regional pattern of [3H]PCP binding but also to bind in other regions not associated with PCP receptors. The results of this study are consistent with the concept that PCP and (+)-SKF10,047 exert their common psychotomimetic and stimulant effects by acting at a common receptor. (+)-SKF10,047 is not a pure ligand of this receptor as it also interacts with a second binding site the behavioral significance of which is as yet unknown.

Original languageEnglish (US)
Pages (from-to)681-688
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume237
Issue number2
StatePublished - 1986
Externally publishedYes

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sigma Receptors
Phencyclidine
Opioid Receptors
Binding Sites
Brain
Haloperidol
Autoradiography
Opiate Alkaloids
Dioxolanes
Phencyclidine Receptors
Ligands
Pentazocine
Tritium
Opioid Analgesics
Microscopy
Light
Proteins

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{4fd090d2946a49719c08fa700be7e635,
title = "Characterization and autoradiographic visualization of (+)-[3H]SKF10,047 binding in rat and mouse brain: Further evidence for phencyclidine/'sigma opiate' receptor commonality",
abstract = "The binding specificity of (+)-[3H]N-allylnormetazocine, the dextrorotatory isomer of the prototypical sigma opiate SKF10,047, was determined in rat and mouse brain and the neuroanatomical distribution of its binding sites elucidated by quantitative autoradiography in sections of rat brain. Computer-assisted Scatchard analysis revealed an apparent two-site fit of the binding data in both species and in all rat brain regions examined. In whole rat brain, the K(d) values were 3.6 and 153 nM and the maximum binding values were 40 fmol and 1.6 pmol/mg of protein for the apparent high- and low-affinity binding sites, respectively. (+)-SKF-10,047, haloperidol and pentazocine were among the most potent inhibitors of 7 nM (+)-[3H]SKF10,047 binding to the higher affinity sites; rank orders of ligand potencies at these sites differ sharply from those that have been reported for the [3H]phencyclidine (PCP) site, or for eliciting PCP-like or SKF10,047-like behaviors. By contrast, rank orders of potency of sigma opioids, PCP derivatives and dioxolanes for displacement of 100 nM (+)-3H]SKF10,047 from the more numerous lower affinity sites in the presence of 100 nM haloperidol agreed closely with their potencies in the [3H]PCP binding assay as well as their potencies in exerting PCP- or SKF10,047-like behavioral effects. In order to compare directly the anatomical localizations of PCP and (+)-SKF10,047 binding sites, quantitative light microscopy autoradiography utilizing tritium-labeled PCP and (+)-SKF10,047 was carried out in rat brain sections. (+)-[3H]SKF10,047 binding was observed to follow the regional pattern of [3H]PCP binding but also to bind in other regions not associated with PCP receptors. The results of this study are consistent with the concept that PCP and (+)-SKF10,047 exert their common psychotomimetic and stimulant effects by acting at a common receptor. (+)-SKF10,047 is not a pure ligand of this receptor as it also interacts with a second binding site the behavioral significance of which is as yet unknown.",
author = "R. Sircar and R. Nichtenhauser and Ieni, {J. R.} and Zukin, {S. R.}",
year = "1986",
language = "English (US)",
volume = "237",
pages = "681--688",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "2",

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TY - JOUR

T1 - Characterization and autoradiographic visualization of (+)-[3H]SKF10,047 binding in rat and mouse brain

T2 - Further evidence for phencyclidine/'sigma opiate' receptor commonality

AU - Sircar, R.

AU - Nichtenhauser, R.

AU - Ieni, J. R.

AU - Zukin, S. R.

PY - 1986

Y1 - 1986

N2 - The binding specificity of (+)-[3H]N-allylnormetazocine, the dextrorotatory isomer of the prototypical sigma opiate SKF10,047, was determined in rat and mouse brain and the neuroanatomical distribution of its binding sites elucidated by quantitative autoradiography in sections of rat brain. Computer-assisted Scatchard analysis revealed an apparent two-site fit of the binding data in both species and in all rat brain regions examined. In whole rat brain, the K(d) values were 3.6 and 153 nM and the maximum binding values were 40 fmol and 1.6 pmol/mg of protein for the apparent high- and low-affinity binding sites, respectively. (+)-SKF-10,047, haloperidol and pentazocine were among the most potent inhibitors of 7 nM (+)-[3H]SKF10,047 binding to the higher affinity sites; rank orders of ligand potencies at these sites differ sharply from those that have been reported for the [3H]phencyclidine (PCP) site, or for eliciting PCP-like or SKF10,047-like behaviors. By contrast, rank orders of potency of sigma opioids, PCP derivatives and dioxolanes for displacement of 100 nM (+)-3H]SKF10,047 from the more numerous lower affinity sites in the presence of 100 nM haloperidol agreed closely with their potencies in the [3H]PCP binding assay as well as their potencies in exerting PCP- or SKF10,047-like behavioral effects. In order to compare directly the anatomical localizations of PCP and (+)-SKF10,047 binding sites, quantitative light microscopy autoradiography utilizing tritium-labeled PCP and (+)-SKF10,047 was carried out in rat brain sections. (+)-[3H]SKF10,047 binding was observed to follow the regional pattern of [3H]PCP binding but also to bind in other regions not associated with PCP receptors. The results of this study are consistent with the concept that PCP and (+)-SKF10,047 exert their common psychotomimetic and stimulant effects by acting at a common receptor. (+)-SKF10,047 is not a pure ligand of this receptor as it also interacts with a second binding site the behavioral significance of which is as yet unknown.

AB - The binding specificity of (+)-[3H]N-allylnormetazocine, the dextrorotatory isomer of the prototypical sigma opiate SKF10,047, was determined in rat and mouse brain and the neuroanatomical distribution of its binding sites elucidated by quantitative autoradiography in sections of rat brain. Computer-assisted Scatchard analysis revealed an apparent two-site fit of the binding data in both species and in all rat brain regions examined. In whole rat brain, the K(d) values were 3.6 and 153 nM and the maximum binding values were 40 fmol and 1.6 pmol/mg of protein for the apparent high- and low-affinity binding sites, respectively. (+)-SKF-10,047, haloperidol and pentazocine were among the most potent inhibitors of 7 nM (+)-[3H]SKF10,047 binding to the higher affinity sites; rank orders of ligand potencies at these sites differ sharply from those that have been reported for the [3H]phencyclidine (PCP) site, or for eliciting PCP-like or SKF10,047-like behaviors. By contrast, rank orders of potency of sigma opioids, PCP derivatives and dioxolanes for displacement of 100 nM (+)-3H]SKF10,047 from the more numerous lower affinity sites in the presence of 100 nM haloperidol agreed closely with their potencies in the [3H]PCP binding assay as well as their potencies in exerting PCP- or SKF10,047-like behavioral effects. In order to compare directly the anatomical localizations of PCP and (+)-SKF10,047 binding sites, quantitative light microscopy autoradiography utilizing tritium-labeled PCP and (+)-SKF10,047 was carried out in rat brain sections. (+)-[3H]SKF10,047 binding was observed to follow the regional pattern of [3H]PCP binding but also to bind in other regions not associated with PCP receptors. The results of this study are consistent with the concept that PCP and (+)-SKF10,047 exert their common psychotomimetic and stimulant effects by acting at a common receptor. (+)-SKF10,047 is not a pure ligand of this receptor as it also interacts with a second binding site the behavioral significance of which is as yet unknown.

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