Blockade of morphine reward through the activation of κ-opioid receptors in mice

Abstract

The effects of systemic (s.c.) treatment with the κ-agonists U-50,488H and E-2078 (a stable dynorphin analog) on the morphine-induced place preference were examined in mice. Morphine (s.c.) caused a dose-related preference for the drug-associated place; the effects at doses of 3 and 5 mg/kg were significant. On the other hand, U-50,488H or E-2078 produced a dose-related conditioned place aversion. Both U-50,488H (1 mg/kg, s.c.) and E-2078 (0.1 mg/kg, s.c.) induced a slight, nonsignificant place aversion. Pretreatment with U-50,488H (1 mg/kg) abolished the morphine (3 mg/kg)-induced place preference. The morphine-induced place preference was also significantly decreased by pretreatment with E-2078 (0.1 mg/kg). The inhibitory effects of the κ-agonists were antagonized by the κ-antagonist nor-binaltorphimine (nor-BNI; 3 mg/kg, s.c.). In contrast, pretreatment with U-50,488H did not affect the place preference induced by the dopamine (DA) receptor agonist apomorphine (1 mg/kg, s.c.). In addition, morphine (3 mg/kg, s.c.) significantly increased the levels of the DA metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the limbic forebrain (nucleus accumbens and olfactory tubercle) but not in the striatum, implying that activation of the mesolimbic DA system may play an important role in the morphine-induced place preference in mice. Pretreatment with U-50,488H significantly reduced the morphine-induced elevation of DA metabolites in the limbic forebrain. These results suggest that κ-agonists suppress the morphine-induced place preference, and that activation of κ-opioid receptors could suppress the reinforcing effects of morphine which may be induced by enhanced DA transmission in the mesolimbic DA system.