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01 August 2010

Long-term adaptation to high doses of morphine causes desensitization of micro-OR- and delta-OR-stimulated G-protein response in forebrain cortex but does not decrease the amount of G-protein alpha subunits

Lenka BourovaBCDE, Miroslava VosahlikovaBD, Dmytro KaganB, Katerina DlouhaBD, Jiri NovotnyBF, Petr SvobodaACDEFG

Med Sci Monit 2010; 16(8): BR260-270 :: ID: 881099

Abstract

Background: The functional activity of trimeric guanine-nucleotide-binding proteins (G-proteins) represents an essential step in linking and regulation of the opioid receptor (micro-,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 micro-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 micro-OR and delta-OR.

Keywords: Morphine - pharmacology, Guanosine Diphosphate - metabolism, Guanosine 5'-O-(3-Thiotriphosphate) - metabolism, GTP-Binding Protein alpha Subunits - metabolism, Enkephalin, Ala(2)-MePhe(4)-Gly(5)- - pharmacology, Drug Tolerance, Dose-Response Relationship, Drug, Cerebral Cortex - metabolism, Cell Membrane - enzymology, Behavior, Animal - drug effects, Baclofen - pharmacology, Adaptation, Physiological - drug effects, Rats, Wistar, Receptors, Opioid, delta - metabolism, Receptors, Opioid, mu - metabolism, Substance Withdrawal Syndrome - physiopathology, Time Factors

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Medical Science Monitor eISSN: 1643-3750
Medical Science Monitor eISSN: 1643-3750