The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse

Abstract

Background Initial hypotheses regarding the role of the κ opioid system in drug addiction suggested that κ receptor stimulation had anti-addictive effects. However, recent research suggests that κ receptor antagonists may reverse motivational aspects of dependence. In the present review, we revisit the studies that measured the effects of κ receptor ligands on the reinforcing and rewarding effects of drugs and postulate underlying neurobiological mechanisms for these effects to elaborate a more complex view of the role of κ receptor ligands in drug addiction. Results The review of studies indicates that κ receptor stimulation generally antagonizes the acute reinforcing/rewarding effects of drugs whereas κ receptor blockade has no consistent effect. However, in a drug dependent-like state, κ receptor blockade was effective in reducing increased drug intake. In animal models of reinstatement, κ receptor stimulation can induce reinstatement via a stress-like mechanism. Results in conditioned place preference/aversion and intracranial self-stimulation indicate that κ receptor agonists produce, respectively, aversive-like and dysphoric-like effects. Additionally, preclinical and postmortem studies show that administration or self-administration of cocaine, ethanol, and heroin activate the κ opioid system. Conclusion κ receptor agonists antagonize the reinforcing/rewarding effects of drugs possibly through punishing/aversive-like effects and reinstate drug seeking through stress-like effects. Evidence suggests that abused drugs activate the κ opioid system, which may play a key role in motivational aspects of dependence. Kappa opioid systems may have an important role in driving compulsive drug intake.