Deletion of guanine nucleotide binding protein az subunit in mice induces a gene dose dependent tolerance to morphine

Leck, KJ, Bartlett, SE, Smith, MT, Megirian, D, Holgate, J, Powell, KL, Matthaei, KI and Hendry, IA (2004) Deletion of guanine nucleotide binding protein az subunit in mice induces a gene dose dependent tolerance to morphine. Neuropharmacology, 46 6: 836-846. doi:10.1016/j.neuropharm.2003.11.024


Author Leck, KJ
Bartlett, SE
Smith, MT
Megirian, D
Holgate, J
Powell, KL
Matthaei, KI
Hendry, IA
Title Deletion of guanine nucleotide binding protein az subunit in mice induces a gene dose dependent tolerance to morphine
Journal name Neuropharmacology   Check publisher's open access policy
ISSN 0028-3908
Publication date 2004
Sub-type Article (original research)
DOI 10.1016/j.neuropharm.2003.11.024
Volume 46
Issue 6
Start page 836
End page 846
Total pages 11
Editor G.L. Collingridge
Place of publication UK
Publisher Pergamon
Collection year 2004
Language eng
Subject C1
320501 Pharmaceutical Sciences and Pharmacy
730104 Nervous system and disorders
Abstract The Mechanism Underlying the development of tolerance to morphine, is still incompletely understood. Morphine binds to opioid receptors, Which in turn activates downstream second messenger cascades through heterotrimeric guanine nucleotide binding proteins (G proteins). In this paper, we show that G(z), a member of the inhibitory G protein family, plays an important role in mediating the analgesic and lethality effects of morphine after tolerance development. We blocked signaling through the G(z) second messenger cascade by genetic ablation of the alpha subunit of the G protein in mice. The Galpha(z) knockout Mouse develops significantly increased tolerance to morphine. which depends oil Galpha(z), gene dosage. Further experiments demonstrate that the enhanced morphine tolerance is not caused by pharmacokinetic and behavioural learning mechanisms. The results suggest that G(z) signaling pathways are involved ill transducing the analgesic and lethality effects of morphine following chronic morphine treatment. (C) 2004 Elsevier Ltd. All rights reserved.
Keyword Neurosciences
Pharmacology & Pharmacy
G Protein
Gz
Opioid
Analgesia
Lethality
Adenylyl-cyclase Supersensitization
Terminal Splice Variants
Opioid-receptor Knockout
Induced Analgesia
Antisense Oligodeoxynucleotides
Periaqueductal Gray
Transducer Proteins
Sex-differences
Alpha-subunits
Mu-receptors
Q-Index Code C1

Document type: Journal Article
Sub-type: Article (original research)
Collections: Excellence in Research Australia (ERA) - Collection
2005 Higher Education Research Data Collection
School of Pharmacy Publications
 
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Created: Wed, 15 Aug 2007, 04:00:31 EST