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

Med Sci Monit. 2010 Aug;16(8):BR260-70.

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 (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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • GTP-Binding Protein alpha Subunits
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Guanosine Diphosphate
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Morphine
  • Baclofen