Abstract
Rationale
The neuropeptide galanin has been shown to modulate opiate dependence and withdrawal. These effects could be mediated via activation of one or more of the three distinct G protein-coupled receptors, namely galanin receptors 1 (GalR1), 2 (GalR2), and 3 (GalR3).
Objectives
In this study, we used several transgenic mouse lines to further define the mechanisms underlying the role played by galanin and its receptors in the modulation of morphine dependence. First, transgenic mice expressing β-galactosidase under the control of the galanin promoter were used to assess the regulation of galanin expression in response to chronic morphine administration and withdrawal. Next, the behavioral responses to chronic morphine administration and withdrawal were tested in mice that over-express galanin, lack the GalR1 gene, or lack the GalR2 gene.
Methods
Transgenic and matched wild-type mice were given increasing doses of morphine followed by precipitation of withdrawal by naloxone and behavioral responses to withdrawal were assessed.
Results
Both morphine administration and withdrawal increased galanin gene transcription in the locus coeruleus (LC). Increasing galanin levels in the brain reduced signs of opiate withdrawal. Mice lacking GalR1 undergo more severe opiate withdrawal, whereas mice lacking GalR2 show no significant difference in withdrawal signs, compare with matched wild-type controls.
Conclusions
Opiate administration and withdrawal increase galanin expression in the LC. Galanin opposes the actions of morphine which leads to opiate dependence and withdrawal, an effect that is mediated via GalR1.
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Abbreviations
- LacZ:
-
β-Galactosidase
- GalR1:
-
Galanin receptor 1
- GalR2:
-
Galanin receptor 2
- GalR3:
-
Galanin receptor 3
- LC:
-
Locus coeruleus
- WT:
-
Wild type
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Acknowledgments
This study was supported by DA15425 (MRP) and NIDA 1RO1DA015425-01A1 subaward (VZ), the Wellcome Trust, and Medical Research Council (DW).
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Holmes, F.E., Armenaki, A., Iismaa, T.P. et al. Galanin negatively modulates opiate withdrawal via galanin receptor 1. Psychopharmacology 220, 619–625 (2012). https://doi.org/10.1007/s00213-011-2515-x
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DOI: https://doi.org/10.1007/s00213-011-2515-x