Morphine desensitization and cellular tolerance are distinguished in rat locus ceruleus neurons

Erica S. Levitt, John Williams

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

μ-Opioid receptor desensitization is considered an initial step in the development of tolerance. Curiously, the commonly used opioid morphine produces robust tolerance but minimal acute desensitization. This study was designed to test the hypothesis that desensitization is indeed present in morphine-treated animals and is distinguished from cellular tolerance by time course of recovery and mechanism. To induce tolerance, rats were treated with continuously released morphine for 1 week. Morphine-mediated activation of G protein-coupled inwardly rectifying potassium conductance was measured using voltage-clamp recordings from locus ceruleus neurons in brain slices from naive or morphine-treated rats. Cellular tolerance was observed as a decrease in morphine efficacy in slices from morphine-treated rats. This tolerance persisted for at least 6 h. An additional reduction in morphine-mediated current was observed when slices from morphine-treated rats were continuously maintained in morphine at approximately the circulating plasma concentration. This additional reduction recovered within 1 h after removal of morphine from the slice and represents desensitization that developed in the tolerant animal. Recovery from desensitization, but not long-lasting tolerance, was facilitated by protein phosphatase 1 (PP1) activity. Furthermore, desensitization, but not tolerance, was reversed by protein kinase C (PKC) inhibitor but not by an inhibitor of c-Jun N-terminal kinase. Therefore, morphine treatment leads to both long-lasting cellular tolerance and readily reversible desensitization, which are differentially dependent on PP1 and PKC activity and combine to result in a substantial decrease in morphine effectiveness. This PKC-mediated desensitization may contribute to the previously reported PKC-dependent reversal of behavioral tolerance.

Original languageEnglish (US)
Pages (from-to)983-992
Number of pages10
JournalMolecular Pharmacology
Volume82
Issue number5
DOIs
StatePublished - Nov 2012

Fingerprint

Locus Coeruleus
Morphine
Neurons
Protein Kinase C
Protein Phosphatase 1
Protein C Inhibitor
JNK Mitogen-Activated Protein Kinases
Opioid Receptors
Protein Kinase Inhibitors
GTP-Binding Proteins
Opioid Analgesics
Potassium

ASJC Scopus subject areas

  • Pharmacology
  • Molecular Medicine

Cite this

Morphine desensitization and cellular tolerance are distinguished in rat locus ceruleus neurons. / Levitt, Erica S.; Williams, John.

In: Molecular Pharmacology, Vol. 82, No. 5, 11.2012, p. 983-992.

Research output: Contribution to journalArticle

@article{466a6033f6794becbd2bd9fe53d5ba1d,
title = "Morphine desensitization and cellular tolerance are distinguished in rat locus ceruleus neurons",
abstract = "μ-Opioid receptor desensitization is considered an initial step in the development of tolerance. Curiously, the commonly used opioid morphine produces robust tolerance but minimal acute desensitization. This study was designed to test the hypothesis that desensitization is indeed present in morphine-treated animals and is distinguished from cellular tolerance by time course of recovery and mechanism. To induce tolerance, rats were treated with continuously released morphine for 1 week. Morphine-mediated activation of G protein-coupled inwardly rectifying potassium conductance was measured using voltage-clamp recordings from locus ceruleus neurons in brain slices from naive or morphine-treated rats. Cellular tolerance was observed as a decrease in morphine efficacy in slices from morphine-treated rats. This tolerance persisted for at least 6 h. An additional reduction in morphine-mediated current was observed when slices from morphine-treated rats were continuously maintained in morphine at approximately the circulating plasma concentration. This additional reduction recovered within 1 h after removal of morphine from the slice and represents desensitization that developed in the tolerant animal. Recovery from desensitization, but not long-lasting tolerance, was facilitated by protein phosphatase 1 (PP1) activity. Furthermore, desensitization, but not tolerance, was reversed by protein kinase C (PKC) inhibitor but not by an inhibitor of c-Jun N-terminal kinase. Therefore, morphine treatment leads to both long-lasting cellular tolerance and readily reversible desensitization, which are differentially dependent on PP1 and PKC activity and combine to result in a substantial decrease in morphine effectiveness. This PKC-mediated desensitization may contribute to the previously reported PKC-dependent reversal of behavioral tolerance.",
author = "Levitt, {Erica S.} and John Williams",
year = "2012",
month = "11",
doi = "10.1124/mol.112.081547",
language = "English (US)",
volume = "82",
pages = "983--992",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "5",

}

TY - JOUR

T1 - Morphine desensitization and cellular tolerance are distinguished in rat locus ceruleus neurons

AU - Levitt, Erica S.

AU - Williams, John

PY - 2012/11

Y1 - 2012/11

N2 - μ-Opioid receptor desensitization is considered an initial step in the development of tolerance. Curiously, the commonly used opioid morphine produces robust tolerance but minimal acute desensitization. This study was designed to test the hypothesis that desensitization is indeed present in morphine-treated animals and is distinguished from cellular tolerance by time course of recovery and mechanism. To induce tolerance, rats were treated with continuously released morphine for 1 week. Morphine-mediated activation of G protein-coupled inwardly rectifying potassium conductance was measured using voltage-clamp recordings from locus ceruleus neurons in brain slices from naive or morphine-treated rats. Cellular tolerance was observed as a decrease in morphine efficacy in slices from morphine-treated rats. This tolerance persisted for at least 6 h. An additional reduction in morphine-mediated current was observed when slices from morphine-treated rats were continuously maintained in morphine at approximately the circulating plasma concentration. This additional reduction recovered within 1 h after removal of morphine from the slice and represents desensitization that developed in the tolerant animal. Recovery from desensitization, but not long-lasting tolerance, was facilitated by protein phosphatase 1 (PP1) activity. Furthermore, desensitization, but not tolerance, was reversed by protein kinase C (PKC) inhibitor but not by an inhibitor of c-Jun N-terminal kinase. Therefore, morphine treatment leads to both long-lasting cellular tolerance and readily reversible desensitization, which are differentially dependent on PP1 and PKC activity and combine to result in a substantial decrease in morphine effectiveness. This PKC-mediated desensitization may contribute to the previously reported PKC-dependent reversal of behavioral tolerance.

AB - μ-Opioid receptor desensitization is considered an initial step in the development of tolerance. Curiously, the commonly used opioid morphine produces robust tolerance but minimal acute desensitization. This study was designed to test the hypothesis that desensitization is indeed present in morphine-treated animals and is distinguished from cellular tolerance by time course of recovery and mechanism. To induce tolerance, rats were treated with continuously released morphine for 1 week. Morphine-mediated activation of G protein-coupled inwardly rectifying potassium conductance was measured using voltage-clamp recordings from locus ceruleus neurons in brain slices from naive or morphine-treated rats. Cellular tolerance was observed as a decrease in morphine efficacy in slices from morphine-treated rats. This tolerance persisted for at least 6 h. An additional reduction in morphine-mediated current was observed when slices from morphine-treated rats were continuously maintained in morphine at approximately the circulating plasma concentration. This additional reduction recovered within 1 h after removal of morphine from the slice and represents desensitization that developed in the tolerant animal. Recovery from desensitization, but not long-lasting tolerance, was facilitated by protein phosphatase 1 (PP1) activity. Furthermore, desensitization, but not tolerance, was reversed by protein kinase C (PKC) inhibitor but not by an inhibitor of c-Jun N-terminal kinase. Therefore, morphine treatment leads to both long-lasting cellular tolerance and readily reversible desensitization, which are differentially dependent on PP1 and PKC activity and combine to result in a substantial decrease in morphine effectiveness. This PKC-mediated desensitization may contribute to the previously reported PKC-dependent reversal of behavioral tolerance.

UR - http://www.scopus.com/inward/record.url?scp=84867799985&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867799985&partnerID=8YFLogxK

U2 - 10.1124/mol.112.081547

DO - 10.1124/mol.112.081547

M3 - Article

C2 - 22914548

AN - SCOPUS:84867799985

VL - 82

SP - 983

EP - 992

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 5

ER -