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β-Arrestin-2 knockout prevents development of cellular μ-opioid receptor tolerance but does not affect

M Connor1, E E Bagley, B C Chieng

  • 1Australian School of Advanced Medicine, Macquarie University, Sydney, NSW, Australia.

British Journal of Pharmacology
|March 7, 2014
PubMed
Abstract

Insights

Beta-arrestin-2 knockout mice show blunted tolerance to morphine

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Opioid tolerance and withdrawal are complex phenomena.
  • Periaqueductal grey (PAG) neurons are critical for these processes.
  • Beta-arrestin-2's role in cellular mechanisms of opioid tolerance and withdrawal is not fully understood.

Purpose of the Study:

  • To investigate the role of beta-arrestin-2 in cellular mechanisms of morphine tolerance and withdrawal.
  • To examine opioid receptor signaling in periaqueductal grey (PAG) neurons from beta-arrestin-2 knockout mice.

Main Methods:

  • Patch-clamp recordings were used to assess mu-opioid receptor (MOPr) inhibition of calcium channel currents (ICa).
  • Experiments were conducted on acutely dissociated PAG neurons from wild-type and beta-arrestin-2 knockout mice.
  • Chronic morphine treatment (CMT) was administered to induce tolerance.

Main Results:

  • Beta-arrestin-2 deletion did not affect MOPr inhibition of ICa in PAG neurons.
  • CMT impaired MOPr-ICa coupling in wild-type mice, but not in beta-arrestin-2 knockout mice, indicating a lack of cellular tolerance.
  • Opioid withdrawal-induced activation of GABA transporter type 1 (GAT-1) currents was similar in both genotypes.

Conclusions:

  • Beta-arrestin-2 is essential for the development of cellular tolerance to morphine in central anti-nociceptive neurons.
  • Opioid withdrawal is not disrupted by the absence of beta-arrestin-2.
  • Basal MOPr sensitivity in PAG neurons is not altered by beta-arrestin-2 deletion.
Keywords:
arrestinsmorphineopioid toleranceopioid withdrawalperiaqueductal greyμ-opioid receptor

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