NDLI: Absence of G-protein activation by μ-opioid receptor agonists in the spinal cord of μ-opioid receptor knockout mice

Content Provider	PubMed Central
Author	Narita, Minoru Mizoguchi, Hirokazu Narita, Michiko Sora, Ichiro Uhl, George R. Tseng, Leon F.
Copyright Year	1999
Abstract	The ability of μ-opioid receptor agonists to activate G-proteins in the spinal cord of μ-opioid receptor knockout mice was examined by monitoring the binding to membranes of the non-hydrolyzable analogue of GTP, guanosine-5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS). In the receptor binding study, Scatchard analysis of [3H][D-Ala2,NHPhe4,Gly-ol]enkephalin ([3H]DAMGO; μ-opioid receptor ligand) binding revealed that the heterozygous μ-knockout mice displayed approximately 40% reduction in the number of μ-receptors as compared to the wild-type mice. The homozygous μ-knockout mice showed no detectable μ-binding sites. The newly isolated μ-opioid peptides endomorphin-1 and -2, the synthetic selective μ-opioid receptor agonist DAMGO and the prototype of μ-opioid receptor agonist morphine each produced concentration-dependent increases in [35S]GTPγS binding in wild-type mice. This stimulation was reduced by 55–70% of the wild-type level in heterozygous, and virtually eliminated in homozygous knockout mice. No differences in the [35S]GTPγS binding stimulated by specific δ1- ([D-Pen2,5]enkephalin), δ2- ([D-Ala2]deltorphin II) or κ1- (U50,488H) opioid receptor agonists were noted in mice of any of the three genotypes. The data clearly indicate that μ-opioid receptor gene products play a key role in G-protein activation by endomorphins, DAMGO and morphine in the mouse spinal cord. They support the idea that μ-opioid receptor densities could be rate-limiting steps in the G-protein activation by μ-opioid receptor agonists in the spinal cord. These thus indicate a limited physiological μ-receptor reserve. Furthermore, little change in δ1-, δ2- or κ1-opioid receptor-G-protein complex appears to accompany μ-opioid receptor gene deletions in this region.
Related Links	http://dx.doi.org/10.1038/sj.bjp.0702330
Ending Page	456
Page Count	6
Starting Page	451
File Format	PDF
ISSN	00071188
Journal	British Journal of Pharmacology
Issue Number	2
Volume Number	126
Language	English
Publisher Date	1999-01-01
Access Restriction	Open
Subject Keyword	Pharmacology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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