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

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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.

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Abbreviations

Positive reinforcement:

defined as the process by which presentation of a stimulus (drug) increases the probability of a response (nondependent drug-taking paradigms)

Punishment:

defined as the process by which presentation of a stimulus (drug) decreases the probability of a response (nondependent drug-taking paradigms)

Negative reinforcement:

defined as a process by which removal of an aversive stimulus (negative emotional state of drug withdrawal) increases the probability of a response (dependence-induced drug taking)

Reward:

defined as a stimulus (drug) that increases the probability of a response, but usually includes a positive hedonic connotation

Stress:

anything that causes an alteration in psychological homeostatic processes

Neuroadaptation:

changes in function of a given neuronal system to a drug

Noxious (aversive) stimulus:

stimuli that arouse emotional reactions of distress, and the termination of them induces relief

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Acknowledgments

We gratefully acknowledge the assistance of Mike Arends in the preparation of the manuscript. We thank Dr. Brendan Walker for discussions and stimulating our interest in the kappa opioid system. This is publication number 20445 from The Scripps Research Institute. Preparation of this manuscript was supported by National Institutes of Health grants DA04043 (G.F.K.), DA04398 (G.F.K.) and DA025785 (S.W.) from the National Institute on Drug Abuse.

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Wee, S., Koob, G.F. The role of the dynorphin–κ opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology 210, 121–135 (2010). https://doi.org/10.1007/s00213-010-1825-8

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