Long-term adaptation to high doses of morphine causes desensitization of mu-OR- and delta-OR-stimulated G-protein response in forebrain cortex but does not decrease the amount of G-protein alpha subunits
Language English Country United States Media print
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
20671607
PII: 881099
Knihovny.cz E-resources
- MeSH
- Substance Withdrawal Syndrome physiopathology MeSH
- Baclofen pharmacology MeSH
- Cell Membrane drug effects enzymology MeSH
- Time Factors MeSH
- Behavior, Animal drug effects MeSH
- Enkephalin, Ala(2)-MePhe(4)-Gly(5)- pharmacology MeSH
- Adaptation, Physiological drug effects MeSH
- Guanosine 5'-O-(3-Thiotriphosphate) metabolism MeSH
- Guanosine Diphosphate metabolism MeSH
- Rats MeSH
- Morphine administration & dosage pharmacology MeSH
- Cerebral Cortex drug effects metabolism MeSH
- Rats, Wistar MeSH
- GTP-Binding Protein alpha Subunits metabolism MeSH
- Receptors, Opioid, delta agonists metabolism MeSH
- Receptors, Opioid, mu agonists metabolism MeSH
- Drug Tolerance MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Baclofen MeSH
- Enkephalin, Ala(2)-MePhe(4)-Gly(5)- MeSH
- Guanosine 5'-O-(3-Thiotriphosphate) MeSH
- Guanosine Diphosphate MeSH
- Morphine MeSH
- GTP-Binding Protein alpha Subunits MeSH
- Receptors, Opioid, delta MeSH
- Receptors, Opioid, mu MeSH
BACKGROUND: The functional activity of trimeric guanine-nucleotide-binding proteins (G-proteins) represents an essential step in linking and regulation of the opioid receptor (mu-, delta- and kappa-OR)-initiated signaling pathways. Theoretical basis and/or molecular mechanism(s) of opioid tolerance and addiction proceeding in the central nervous system were not studied in the forebrain cortex of mammals with respect to quantitative analysis of opioid-stimulated trimeric G-protein activity. MATERIAL/METHODS: G-protein activity was measured in PercollR-purified plasma membranes (PM) isolated from the frontal brain cortex of control and morphine-treated rats by both high-affinity [32P]GTPase and [35S]GTPgammaS binding assays. Exposition to morphine was performed by intra-muscular application of this drug. Control animals were injected with sterile PBS. RESULTS: Both mu-OR (DAMGO)- and delta-OR (DADLE)-responses were clearly desensitized in PM isolated from morphine-treated rats; kappa-OR (U-69593)- and baclofen (GABAB-R)-stimulated [35S]GTPgammaS binding was unchanged, indicating the specificity of the morphine effect. Under such conditions, the amount of G-protein alpha subunits was unchanged. The order of efficacy DADLE>DAMGO>U-69593 was the same in control and morphine-treated PM. Behavioral tests indicated that morphine-treated animals were fully drug-dependent and developed tolerance to subsequent drug addition. CONCLUSIONS: Prolonged exposure of rats to high doses of morphine results in decrease of the over-all output of OR-stimulated G-protein activity in the forebrain cortex but does not decrease the amount of these regulatory proteins. These data support the view that the mechanism of the long-term adaptation to high doses of morphine is primarily based on desensitization of OR-response preferentially oriented to mu-OR and delta-OR.
Expression of Opioid Receptors in Cells of the Immune System
