Different roles of μ-, δ- and κ-opioid receptors in ethanol-associated place preference in rats exposed to conditioned fear stress

Abstract

The present study was designed to investigate the role of the endogenous opioid system in the development of ethanol-induced place preference in rats exposed to conditioned fear stress (exposure to an environment paired previously with electric foot shock), using the conditioned place preference paradigm. The administration of ethanol (300 mg/kg, i.p.) with conditioned fear stress induced significant place preference. Naloxone (1 and 3 mg/kg, s.c.), a non-selective opioid receptor antagonist, significantly attenuated this ethanol-induced place preference. Moreover, the selective μ-opioid receptor antagonist β-funaltrexamine (3 and 10 mg/kg, i.p.) and the selective δ-opioid receptor antagonist naltrindole (1 and 3 mg/kg, s.c.) significantly attenuated ethanol-induced place preference. In contrast, the selective κ-opioid receptor antagonist nor-binaltorphimine (3 mg/kg, i.p.) significantly enhanced ethanol-induced place preference. Furthermore, 75 mg/kg ethanol (which tended to produce place preference) combined with the μ-opioid receptor agonist morphine (0.1 mg/kg, s.c.) or the selective δ-opioid receptor agonist 2-methyl-4aα-(3-hydroxyphenyl)-1,2,3,4,4a,5,12,12aα-octahydroquinolino [2,3,3,- g] isoquinoline (TAN-67; 20 mg/kg, s.c.), at doses which alone did not produce place preference, produced significant place preference. However, co-administration of the selective κ-opioid receptor agonist trans-3,4-dichloro- N-(2-(1-pyrrolidinyl)cyclohexyl)benzenacetamide methanesulfonate (U50,488H; 0.3 and 1 mg/kg, s.c.) with ethanol (300 mg/kg, i.p.) dose dependently attenuated ethanol-induced place preference. Moreover, conditioned fear stress shifted the response curve for the aversive effect of U50,488H to the left. These results suggest that μ- and δ-opioid receptors may play critical roles in the rewarding mechanism of ethanol, and that κ-opioid receptors may modulate the development of the rewarding effect of ethanol under psychological stress.