Opioid receptors: drivers to addiction?

Abstract

Drug addiction is a worldwide societal problem and public health burden, and results from recreational drug use that develops into a complex brain disorder. The opioid system, one of the first discovered neuropeptide systems in the history of neuroscience, is central to addiction. Recently, opioid receptors have been propelled back on stage by the rising opioid epidemics, revolutions in G protein-coupled receptor research and fascinating developments in basic neuroscience. This Review discusses rapidly advancing research into the role of opioid receptors in addiction, and addresses the key questions of whether we can kill pain without addiction using mu-opioid-receptor-targeting opiates, how mu- and kappa-opioid receptors operate within the neurocircuitry of addiction and whether we can bridge human and animal opioid research in the field of drug abuse.

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Fig. 1: Opioid receptor structure and signalling.
Fig. 2: Opioid receptors in physiology and addiction.

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Acknowledgements

The authors deeply thank the CNRS/INSERM/University of Strasbourg (France), the US National Institutes of Health (National Institute of Drug Abuse Grant 05010 and National Institute on Alcohol Abuse and Alcoholism Grant 16658 to B.L.K.), the Canada Fund for Innovation and the Canada Research Chairs (to B.L.K and E.D.), and the Bourgeois family (B.L.K. is the Bourgeois Chair for Pervasive Developmental Disorders) for continuous support.

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Nature Reviews Neuroscience thanks E. J. Nestler and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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E.D. and B.L.K. researched data for the article, made substantial contributions to the discussion of content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Brigitte Lina Kieffer.

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Glossary

Psychotomimetic

An effect caused by drugs, mimicking symptoms of psychosis, such as agitation, delusions and delirium.

Biased agonism

A signalling response determined by the conformation of the drug–receptor–effector complex that engages only a subset of cellular effectors. Some high-throughput screening programmes have aimed to design novel ‘biased’ drugs with improved therapeutic profiles.

Therapeutic window

Dose range for a drug that allows therapeutic efficacy with no (or minimal) side effects.

Location bias

Bias in receptor signalling dictated by the location of the receptor in the cell (for example, at the surface or in endosomes or Golgi) and the availability of effectors at this site.

Systems bias

Bias in receptor signalling driven by anatomical localization within brain circuits subserving the behavioural response and the effectors available at those sites.

Precision medicine

Also known as personalized medicine. An innovative approach in medicine in which interindividual variability (in lifestyle, environment and genes) is taken into consideration for disease prevention and/or treatment.

Hedonic balance

The equilibrium between positive and negative affect. A positive hedonic state is considered a state of well-being, whereas a negative hedonic state is unpleasant.

Reverse pharmacology

An approach in which a receptor or endogenous ligand is discovered first, the physiological function is determined.

Conditioned place preference

(CPP). A behavioural paradigm in rodents that determines the rewarding or aversive effect of a drug on the basis of time spent in a drug-associated context after conditioning.

Tetrahydrocannabinol

(THC). The principal psychoactive component of cannabis, which produces central effects by acting at cannabinoid CB1 receptors.

Psychostimulants

A group of substances (including cocaine and amphetamines) that enhance physical and cognitive performance. Psychostimulants are used to treat attention deficit–hyperactivity disorder.

Inhibitory controls

A central component of executive functions, geared to inhibit or delay dominant responses to achieve a goal.

Operant photostimulation

Instrumental conditioning in which animals learn to self-administer optogenetic stimulation; used to determine whether a neuronal population mediates reward.

Escalation

In animal research, extended access to the drug leads to a daily increase (or escalation) of drug intake, which is suggested to reflect loss of control.

Quantitative trait loci

Genomic regions that carry one or more DNA mutations that correlate with phenotypic variations (for example, behaviour, gene expression and protein levels).

Machine learning

A research field in which computers learn to extract patterns from complex data sets without being explicitly programmed for this goal. Helps biologists to build predictions.

Receptor bioavailability

Also known as receptor binding. The quantity of radiotracer that binds to its target receptor in positron emission tomography imaging. Depends on receptor levels and occupancy by endogenous ligands.

Effective connectivity

In functional MRI, a measure of the influence of one brain region on the activity of another brain region.

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Darcq, E., Kieffer, B.L. Opioid receptors: drivers to addiction?. Nat Rev Neurosci 19, 499–514 (2018). https://doi.org/10.1038/s41583-018-0028-x

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