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The neural circuits and signalling pathways of opioid use disorder

Nature Reviews Neuroscience volume 26, pages 778–797 (2025)Cite this article

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Abstract

The increasing prevalence of opioid use disorder (OUD) represents an important global public health crisis, often referred to as the ‘opioid epidemic’. Opioids are known for their potent pain-relieving effects, but also have serious side effects, including OUD and respiratory depression, which can lead to fatal overdoses. To address this growing concern, we require a better understanding of the mechanisms underlying OUD, which typically begins with either medical or recreational opioid use and evolves into a complex and chronic brain disorder. In this Review, we highlight recent advances in our understanding of opioid receptors and the neural circuits in which they operate (including the broad network of circuits involved in reward and relief processing), focusing on the changes that follow long-term opioid exposure, abstinence and withdrawal. Additionally, we discuss recent findings that highlight the importance of the local cellular environment in shaping responses to these drugs. Overall, we aim to provide an updated overview of the field that may give us new insights into the multifaceted landscape of OUD.

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Fig. 1: The opioid system.
Fig. 2: Conceptual framework for opioid use disorder.
Fig. 3: Neurobiological circuits implicated in opioid use disorder.
Fig. 4: New tools to investigate the molecular signalling of opioid receptors.

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Acknowledgements

The authors sincerely thank B. L. Kieffer for her support throughout various stages of their careers and for inspiring them with her ardent passion for opioid research. The authors acknowledge the permanent support of INSERM and University of Strasbourg (UNISTRA, France). This work was also supported by the University of Strasbourg Initiative of Excellence (to E.D.), the National Institutes of Mental Health (K01MH123757 to A.T.E.), Agence National de la recherche (ANR-23-CE16-0016 to E.D. and ANR-24-CE37-3736 to E.D.), Institut pour la Recherche en Santé Publique (SPAV1-22-018 to E.D. and IRESP-AAP-2023-SPA-3 to V.M.) and NEUROSTRA (9R25016SXBSXB to V.M.).

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Authors and Affiliations

  1. INSERM UMR-S1329, Strasbourg Translational Neuroscience & Psychiatry, University of Strasbourg, Strasbourg, France

    Victor P. Mathis & Emmanuel Darcq

  2. Department of Psychiatry and Behavioral Sciences, University of California San Francisco, San Francisco, CA, USA

    Aliza T. Ehrlich

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  1. Victor P. Mathis
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  2. Aliza T. Ehrlich
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  3. Emmanuel Darcq
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The authors contributed equally to all aspects of the article.

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Correspondence to Aliza T. Ehrlich or Emmanuel Darcq.

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Glossary

Anti-reward system activation

The recruitment of brain circuits that at first would limit consumption but in the cycle of OUD might enhance negative emotional states during withdrawal, driving the need for opioids to alleviate discomfort.

Between-system interactions

Interactions between brain systems (groups of brain regions implicated in specific functions) outside the reward pathway that become recruited to counterbalance the overactivation caused by drugs. These are mostly the stress and ’anti-reward’ systems.

Biased signalling

A response shaped by the specific conformation of the drug–receptor–effector complex, which selectively activates only a subset of intracellular effectors. A drug inducing biased signalling is referred to as a biased agonist.

Craving

Drug craving has generally been defined as a desire and urgent need to use a drug. It reflects the desire to feel the effect of a drug (subjective) as well as the intention to use the drug (action).

Escalation of drug intake

A progressive increase in the quantity of a drug consumed over time.

Incentive salience

The process by which an opioid heightens its perceived desirability, even when its consumption is no longer pleasurable.

Liking versus wanting

A divergence whereby the pleasurable effects of opioids (liking) diminish over time, whereas the compulsive desire to seek them (wanting) intensifies.

Location bias

Receptor signalling that is determined by the availability of effectors in the precise location of the receptor, such as a cellular membrane compartment (surface, endosome, primary cilium or Golgi).

Myelin plasticity

The ability of myelin to adapt structurally and functionally in response to neuronal activity and environmental changes.

Opioid-induced hyperalgesia

A paradoxical phenomenon in which, rather than alleviating pain as intended, chronic opioid exposure leads to pain perception in response to otherwise non-painful stimuli.

Tolerance

The weakening of a drug’s effects with repeated exposure. This effect is observable for many substances and not restricted to substances of abuse.

Withdrawal

The symptoms a person experiences when not using a substance. Usual opioid withdrawal symptoms are agitation, anxiety, sleep disturbances, abdominal cramping, nausea, diarrhoea, sweating and muscle aches.

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Mathis, V.P., Ehrlich, A.T. & Darcq, E. The neural circuits and signalling pathways of opioid use disorder. Nat. Rev. Neurosci. 26, 778–797 (2025). https://doi.org/10.1038/s41583-025-00982-7

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