Different roles of mu-, delta- and kappa-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress

The present study was designed to investigate the role of the endogenous op ioid system in the development of ethanol-induced place preference in rats exposed to conditioned fear stress (exposure to an environment paired previ ously with electric foot shock), using the conditioned place preference par adigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fea r stress induced significant place preference. Naloxone (1 and 3 mg/kg, s.c .), a non-selective opioid receptor antagonist, significantly attenuated th is ethanol-induced place preference. Moreover, the selective mu-opioid rece ptor antagonist beta-funaltrexamine (3 and 10 mg/kg, i.p.) and the selectiv e delta-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.) signif icantly attenuated ethanol-induced place preference. In contrast, the selec tive kappa-opioid receptor antagonist nor-binaltorphimine (3 mg/kg, i.p.) s ignificantly enhanced ethanol-induced place preference. Furthermore, 75 mg/ kg ethanol (which tended to produce place preference) combined with the mu- opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective delta-o pioid receptor agonist 2-methyl-4a alpha-(3-hydroxyphenyl)-1,2,3,4,4a,5,12, 12a alpha-octahydroquinolino [2,3,3,-g] isoquinoline (TAN-67; 20 mg/kg, s.c .), at doses which alone did not produce place preference, produced signifi cant place preference. However, co-administration of the selective kappa-op ioid receptor agonist trans-3,4-dichloro-N-(2-(1-pyrrolidinyl)cyclohexyl)be nzenacetamide methanesulfonate (U50,488H; 0.3 and 1 mg/kg, s.c.) with ethan ol (300 mg/kg, i.p.) dose dependently attenuated ethanol-induced place pref erence. Moreover, conditioned fear stress shifted the response curve for th e aversive effect of U50,488H to the left. These results suggest that mu- a nd delta-opioid receptors may play critical roles in the rewarding mechanis m of ethanol, and that kappa-opioid receptors may modulate the development of the rewarding effect of ethanol under psychological stress. (C) 1999 Els evier Science B.V. All rights reserved.