Psychopharmacology

, Volume 228, Issue 2, pp 207–215

Effect of chronic ethanol treatment on μ-opioid receptor function, interacting proteins and morphine-induced place preference

  • Masahiro Shibasaki
  • Kenjiro Watanabe
  • Kotaro Takeda
  • Toshimasa Itoh
  • Tomohisa Tsuyuki
  • Minoru Narita
  • Tomohisa Mori
  • Tsutomu Suzuki
Original Investigation

DOI: 10.1007/s00213-013-3023-y

Cite this article as:
Shibasaki, M., Watanabe, K., Takeda, K. et al. Psychopharmacology (2013) 228: 207. doi:10.1007/s00213-013-3023-y

Abstract

Rationale

Both the acute and chronic consumption of ethanol have been reported to modify several molecular events in the central nervous system, and the endogenous μ-opioid receptor system is involved in the reinforcing/rewarding effects of ethanol.

Objectives

The present study was designed to clarify the effects of chronic ethanol treatment on cellular processes involving μ-opioid receptor and the development of morphine-induced rewarding effects.

Methods

Male C57BL/6J mice were continuously treated with a liquid diet containing 3.0 w/v ethanol. The direct involvement of μ-opioid receptor functions in the activation of G-proteins and changes in protein levels in the lower midbrain of mice after chronic treatment with ethanol were investigated by a [35S] GTPγS binding assay and Western blotting, respectively. The rewarding effects of morphine (5 mg/kg) under treatment with ethanol were measured by the conditioned place preference paradigm.

Results

The function of μ-opioid receptor was increased by treatment with ethanol in the lower midbrain using [35S] GTPγS binding assay. Furthermore, the GRK2 protein level was significantly increased by treatment with ethanol. Chronic treatment with ethanol enhanced the rewarding effects of morphine. On the other hand, this enhancement of the rewarding effects of morphine by ethanol treatment was significantly inhibited by the GRK2 inhibitor β-adrenergic receptor kinase 1 inhibitor.

Conclusions

The present study demonstrated that chronic treatment with ethanol enhanced the rewarding effects of morphine by up-regulating functional changes in μ-opioid receptor, mediated by GRK2.

Keywords

Ethanol Morphine μ-Opioid receptor GRK2 Rewarding effect 

Abbreviations

DAMGO

[d-Ala2-N-Me-Phe4-Gly5-ol]-enkephalin

VTA

Ventral tegmental area

GPCRs

G-protein-coupled receptors

GDP

Guanosine-5′-diphosphate

[35S]GTPγS

Guanosine-5′-O-(3-[35S]thio) triphosphate

GRK2

G-protein-coupled receptor-specific serine/threonine kinase 2

Supplementary material

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ESM 1

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Masahiro Shibasaki
    • 1
  • Kenjiro Watanabe
    • 1
  • Kotaro Takeda
    • 1
  • Toshimasa Itoh
    • 1
  • Tomohisa Tsuyuki
    • 1
  • Minoru Narita
    • 2
  • Tomohisa Mori
    • 1
  • Tsutomu Suzuki
    • 1
  1. 1.Department of ToxicologyHoshi University School of Pharmacy and Pharmaceutical SciencesTokyoJapan
  2. 2.Department of PharmacologyHoshi University School of Pharmacy and Pharmaceutical SciencesTokyoJapan

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