Changes in the expression of G protein-coupled receptor kinases and beta-arrestin 2 in rat brain during opioid tolerance and supersensitivity

J Neurochem. 2001 Apr;77(2):486-92. doi: 10.1046/j.1471-4159.2001.00268.x.

Abstract

We previously demonstrated that chronic treatment of rats with the mu-opioid receptor agonist sufentanil induced pharmacological tolerance associated with mu-opioid receptor desensitization and down-regulation. Administration of the calcium channel blocker nimodipine during chronic treatment with sufentanil prevented mu-opioid receptor down-regulation, induced down-stream supersensitization, and produced supersensitivity to the opioid effects. The focus of the present study was to determine a role for G protein-coupled receptor kinases (GRKs) and beta-arrestin 2 in agonist-induced mu-opioid receptor signalling modulation during chronic opioid tolerance and supersensitivity. Tolerance was induced by 7-day chronic infusion of sufentanil (2 microgram/h). Supersensitivity was induced by concurrent infusion of sufentanil (2 microgram/h) and nimodipine (1 microgram/h) for 7 days. Antinociception was evaluated by the tail-flick test. GRK2, GRK3, GRK6 and beta-arrestin 2 immunoreactivity levels were determined by western blot in brain cortices. Acute and chronic treatment with sufentanil induced analgesic tolerance, associated with up-regulation of GRK2, GRK6, and beta-arrestin 2. GRK3 expression only was increased in the acutely treated group. When nimodipine was associated to the chronic opioid treatment, tolerance expression was prevented, and immunoreactivity levels of GRK2, GRK6 and beta-arrestin 2 recovered the control values. These data indicate that GRK2, GRK3, GRK6 and beta-arrestin 2 are involved in the short- and long-term adaptive changes in mu-opioid receptor activity, contributing to tolerance development in living animals. These observations also suggest that GRKs and beta-arrestin 2 could constitute pharmacological targets to prevent opioid tolerance development, and to improve the analgesic efficacy of opioid drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arrestins / biosynthesis*
  • Arrestins / genetics
  • Blotting, Western
  • Brain / drug effects*
  • Brain / metabolism
  • Calcium Channel Blockers / pharmacology
  • Calcium Channels, L-Type / drug effects
  • Cyclic AMP-Dependent Protein Kinases / biosynthesis*
  • Cyclic AMP-Dependent Protein Kinases / genetics
  • Drug Tolerance
  • Enzyme Induction / drug effects
  • G-Protein-Coupled Receptor Kinase 3
  • G-Protein-Coupled Receptor Kinases
  • Gene Expression Regulation / drug effects
  • Male
  • Narcotics / pharmacology*
  • Nerve Tissue Proteins / biosynthesis*
  • Nerve Tissue Proteins / genetics
  • Nimodipine / pharmacology
  • Protein-Serine-Threonine Kinases / biosynthesis*
  • Protein-Serine-Threonine Kinases / genetics
  • Rats
  • Rats, Wistar
  • Receptors, Opioid, mu / drug effects
  • Sufentanil / pharmacology
  • beta-Adrenergic Receptor Kinases
  • beta-Arrestin 2
  • beta-Arrestins

Substances

  • Arrb2 protein, rat
  • Arrestins
  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Narcotics
  • Nerve Tissue Proteins
  • Receptors, Opioid, mu
  • beta-Arrestin 2
  • beta-Arrestins
  • Nimodipine
  • Sufentanil
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • G-Protein-Coupled Receptor Kinase 3
  • Grk3 protein, rat
  • beta-Adrenergic Receptor Kinases
  • G-Protein-Coupled Receptor Kinases
  • G-protein-coupled receptor kinase 6