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beta-Arrestin2, interacting with phosphodiesterase 4, regulates synaptic release probability and presynaptic

Amyaouch Bradaïa1, Frédérique Berton, Serge Ferrari

  • 1Department of Basic Neurosciences, University of Geneva, CH 1211 Geneva, Switzerland.

Proceedings of the National Academy of Sciences of the United States of America
|February 19, 2005
PubMed

Insights

Beta-arrestin2 normally limits opioid pain relief. Its absence enhances morphine

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Most mu-opioid receptor agonists recruit beta-arrestin2.
  • Morphine's acute analgesic effect is paradoxically enhanced in beta-arrestin2 knockout mice.

Purpose of the Study:

  • To investigate the mechanism behind morphine's enhanced analgesia in beta-arrestin2 knockout mice.
  • To examine the role of beta-arrestin2 in presynaptic inhibition by opioids.

Main Methods:

  • Electrophysiological recordings in acute brain slices of the locus coeruleus and periaqueductal gray.
  • Comparison of wild-type (WT) and beta-arrestin2 knockout (KO) mice.
  • Analysis of evoked and miniature inhibitory postsynaptic currents (IPSCs).

Main Results:

  • Presynaptic inhibition of evoked IPSCs was enhanced in beta-arrestin2 KO mice.
  • Postsynaptic G protein-coupled K(+) (Kir3/GIRK) currents were unaffected.
  • Increased frequency of miniature IPSCs in KO mice indicated higher GABA release probability.
  • Enhanced morphine efficacy to inhibit GABA release was linked to increased cAMP levels and impaired phosphodiesterase 4 function.

Conclusions:

  • Beta-arrestin2 attenuates presynaptic opioid inhibition independently of mu-opioid receptor recruitment.
  • Beta-arrestin2 may be a therapeutic target for modulating opioid analgesia.

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