mu-opioid receptor and alpha2-adrenoceptor agonist stimulation of [35S]GTPgammaS binding to G-proteins in postmortem brains of opioid addicts

Mol Psychiatry. 2000 May;5(3):308-15. doi: 10.1038/sj.mp.4000727.

Abstract

Repeated opioid administration has been associated in human brain with unaltered density of mu-opioid receptors (agonist radioligand binding sites and immunodetected receptor protein). These receptors are coupled to Gi/Go-proteins, which are increased in brain of heroin addicts. To assess the activity of G-proteins and their coupling to receptors after chronic opioid abuse, [35S]GTPgammaS binding was quantified in postmortem prefrontal cortices of 15 opioid-dependent subjects and 15 matched controls. The stimulation of [35S]GTPgammaS binding by the mu-opioid receptor agonist DAMGO or the alpha2-adrenoceptor agonist UK14304 was used as a functional measure of the status of the receptor-G-protein coupling. [35S]GTPgammaS binding basal values were similar in opioid addicts (819+/-83 fmol mg-1 of protein) and controls (918+/-106 fmol mg(-1) of protein). In opioid addicts, [35S]GTPgammaS binding stimulation by DAMGO showed a maximal effect (62+/-8%) and a potency (EC50 = 1.09+/-0.26 microM) that did not differ from the maximal effect (60+/-12%) and potency (EC50 = 2.01+/-0.58 microM) in controls. In opioid addicts, [35S]GTPgammaS binding stimulation by UK14304 was not different in maximal effect (28+/-3%) from controls (32+/-8%), but the potency of the agonist was decreased (EC50 = 4.36+/-1.81 microM) when compared with controls (EC50 = 0.41+/-0.15 microM). The results provide a direct evidence of an apparent normal functional activity of brain mu-opioid receptors (Gi/Go-protein coupling) during the opioid dependence process in humans. The data also demonstrate a functional uncoupling of alpha2-adrenoceptors from G-proteins, which indicates a heterologous desensitization of these receptors. This finding could represent an adaptive mechanism against the decreased noradrenergic activity induced by the chronic presence of opioid drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adrenergic alpha-2 Receptor Agonists*
  • Adrenergic alpha-Agonists / pharmacology
  • Adult
  • Autopsy
  • Brain / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Brimonidine Tartrate
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology*
  • GTP-Binding Proteins / metabolism*
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism*
  • Humans
  • Male
  • Opioid-Related Disorders / metabolism*
  • Opioid-Related Disorders / pathology
  • Postmortem Changes
  • Quinoxalines / pharmacology*
  • Receptors, Opioid, mu / agonists*
  • Reference Values
  • Sulfur Radioisotopes

Substances

  • Adrenergic alpha-2 Receptor Agonists
  • Adrenergic alpha-Agonists
  • Quinoxalines
  • Receptors, Opioid, mu
  • Sulfur Radioisotopes
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Brimonidine Tartrate
  • GTP-Binding Proteins