Involvement of mesolimbic κ-opioid systems in the discriminative stimulus effects of morphine

Abstract

The neuroanatomical basis of opiate addiction has been studied using a variety of behavioural techniques. The aim of the present study was to investigate the role of mesolimbic opioid systems, in particular κ-opioid systems, in the expression of the discriminative stimulus effects of abused drugs. Rats were trained to discriminate morphine (3.0 mg/kg s.c.) from saline under a fixed ratio schedule of food reinforcement. Once rats had acquired the discrimination, a randomized sequence of different doses of the highly selective κ-opioid receptor agonist U69593 (0.02–0.16 mg/kg s.c.) was given 20 min prior to a systemic morphine injection. U69593 dose-dependently blocked the morphine discrimination. It is important to note that U69593 at these doses failed to generalize to the systemic morphine cue. The site of action by U69593 (0.02–0.16 μg) was examined by microinjecting discrete amounts into target brain regions. Intra-nucleus accumbens injections of U69593 dose-dependently blocked the systemic morphine cue, whereas, U69593 failed to generalize to the discriminative stimulus. The same doses did not affect morphine discrimination after intra-ventral tegmental area or striatum injections. Besides the rewarding effects of drugs of abuse, the discriminative stimulus properties of these agents are seen as a major factor in drug seeking behaviours. The present study shows that the discriminative effects of morphine, a measure of the subjective effects of this drug can be blocked by the activation of κ-opioid receptors located in the nucleus accumbens. In view of these findings which show that the activity of endogenous κ-opioid systems (dynorphin) may serve as physiological antagonists to counteract the effects of morphine, κ-agonists therefore may be useful in the treatment of opioid addictions.