Delta-opioid receptor antagonism leads to excessive ethanol consumption in mice with enhanced activity of the endogenous opioid system.
The opioid system modulates the central reinforcing effects of ethanol and participates in the etiology of addiction. However, the pharmacotherapy of ethanol dependence targeted on the opioid system is little effective and varies due to individual patients' sensitivity. In the present study, we used two mouse lines with high (HA) and low (LA) activity of the endogenous opioid system to analyze the effect of opioid receptor blockade on ethanol drinking behavior. We found that LA and HA lines characterized by divergent magnitudes of swim stress-induced analgesia also differ in ethanol intake and preference. Downregulation of the opioid system in LA mice was associated with increased ethanol consumption. Treatment with a non-selective opioid receptor antagonist (naloxone) had no effect on ethanol intake in this line. Surprisingly, in HA mice, the blockage of opioid receptors led to excessive ethanol consumption. Moreover, naloxone selectively induced high levels of anxiety- and depressive-like behaviors in HA mice which was attenuated by ethanol. With the use of specific opioid receptor antagonists we showed that the naloxone-induced increase in ethanol drinking in HA mice is mediated mainly by δ and to a lower extent by μ opioid receptors. The effect of δ-opioid receptor antagonism was abolished in HA mice carrying a C320T transition in the δ-opioid receptor gene (EU446125.1), which impairs this receptor's function. Our results indicate that high activity of the opioid system plays a protective role against ethanol dependence. Therefore, its blockage with opioid receptor antagonists may lead to a profound increase in ethanol consumption.
Laboratory of Neurogenomics and Department of Animal Behaviour, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Postepu 36A Str., 05-552 Magdalenka, Poland.
Piotr
P
Poznanski
Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.
Anna
A
Lesniak
Department of Molecular Neuropharmacology, Institute of Pharmacology, 12 Smetna Str., 31-343 Krakow, Poland.
Michal
M
Korostynski
Department of Molecular Neuropharmacology, Institute of Pharmacology, 12 Smetna Str., 31-343 Krakow, Poland.
Klaudia
K
Szklarczyk
Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, Warsaw, Poland.
Marzena
M
Lazarczyk
Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
Piotr
P
Religa
Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland.
Magdalena
M
Bujalska-Zadrozny
Laboratory of Neurogenomics and Department of Animal Behaviour, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Postepu 36A Str., 05-552 Magdalenka, Poland.
Bogdan
B
Sadowski
Laboratory of Neurogenomics and Department of Animal Behaviour, Institute of Genetics and Animal Breeding, Polish Academy of Sciences, Jastrzebiec, Postepu 36A Str., 05-552 Magdalenka, Poland; Department of Pharmacodynamics, Centre for Preclinical Research and Technology, Medical University of Warsaw, Warsaw, Poland; Department of Internal Medicine, Hypertension and Vascular Diseases, Medical University of Warsaw, Warsaw, Poland. Electronic address: msacharczuk@wum.edu.pl.
Mariusz
M
Sacharczuk
D000428:Alcohol Drinking / Q000235:genetics / Q000503:physiopathology / Q000523:psychology*; D000698:Analgesia; D000704:Analysis of Variance; D000818:Animals; D002492:Central Nervous System Depressants / Q000494:pharmacology; D004195:Disease Models, Animal; D000431:Ethanol / Q000494:pharmacology; D005838:Genotype; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D019964:Mood Disorders / Q000209:etiology / Q000503:physiopathology*; D009019:Morphinans / Q000494:pharmacology; D009270:Naloxone / Q000494:pharmacology*; D009292:Narcotic Antagonists / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013315:Stress, Psychological / Q000235:genetics / Q000503:physiopathology*; D013550:Swimming; D001615:beta-Endorphin / Q000378:metabolism
D002492:Central Nervous System Depressants; D009019:Morphinans; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; C058450:cyprodime; D009270:Naloxone; D000431:Ethanol; D001615:beta-Endorphin
Delta opioid receptors; Ethanol dependence; Naloxone; Opioid system; Selected mouse lines; Stress-induced analgesia