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  • Review Article
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The causal role of brain circuits in osteoarthritis pain

Nature Reviews Rheumatology volume 21, pages 261–274 (2025)Cite this article

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Abstract

Osteoarthritis (OA) is a leading cause of chronic pain worldwide, resulting in substantial disability and placing a substantial burden on patients and society. The hallmark symptom of OA is joint pain. Despite extensive research, new treatments for OA pain remain limited, partly owing to a lack of understanding of underlying pain mechanisms. For a long time, OA pain was seen as a reflection of nociceptive activity at the joint level, and the brain has been viewed as a passive recipient of such information. In this Review, we challenge these concepts and discuss how, over time, the activation of peripheral nociceptors leads to adaptations in the brain that dictate the properties and experience of OA pain. These adaptations are further influenced by the inherent properties of the brain. We review general concepts that distinguish pain from nociception, present evidence on the incongruity between joint injury and experience of OA pain, and review brain circuits that are crucial in the perception of OA pain. Finally, we propose a model that integrates nociception, spinal-cord mechanisms, and central nervous system dynamics, each contributing uniquely to pain perception. This framework has the potential to inform the development of personalized treatment strategies.

Key points

  • Osteoarthritis (OA) commonly leads to chronic pain, and as OA pain becomes clinically apparent over time, brain adaptations to the disease have the potential to shape the characteristics and experience of pain.

  • The brain’s role in OA pain is shaped not only by sensory pathways but also by cognitive appraisal, emotional processing and descending modulation, all of which interact to influence pain perception.

  • Models that integrate the diverse peripheral and central mechanisms of OA pain can uncover key processes, identify therapeutic targets and establish probabilistic approaches for treatment outcomes, potentially paving the way for personalized decision-making.

  • The relative contributions of nociceptive activity, spinal-cord sensitization and supraspinal modulation to OA pain — and to pain relief with treatments — remain to be fully identified, highlighting the need for further scientific efforts to measure their interactions.

  • OA pain treatment might benefit from shifting its focus from primarily targeting the joint to incorporating both peripheral and central neuroplasticity-based interventions.

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Fig. 1: Current challenges in understanding mechanisms of pain in osteoarthritis.
Fig. 2: Brain circuits in osteoarthritis.
Fig. 3: Mechanistic modelling of pain in osteoarthritis.

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Authors and Affiliations

  1. Department of Anaesthesiology and Center for Translational Pain Research, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA

    Joana Barroso, Paulo Branco & A. Vania Apkarian

  2. Department of Physical Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA

    Joana Barroso & A. Vania Apkarian

  3. Department of Neuroscience, Feinberg School of Medicine, Northwestern University, Evanston, IL, USA

    A. Vania Apkarian

Authors
  1. Joana Barroso
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  2. Paulo Branco
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  3. A. Vania Apkarian
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The authors contributed equally to all aspects of the article.

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Correspondence to Paulo Branco or A. Vania Apkarian.

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Nature Reviews Rheumatology thanks Anna Woodbury, who co-reviewed with Jason Ramos, and the other, anonymous, reviewers for their contribution to the peer review of this work.

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Glossary

Amygdala

A brain structure located in the medial temporal lobe, crucial for processing emotions such as fear, anxiety and pain. The amygdala has a key role in threat assessment, emotional memory formation and behaviours associated with reward and reinforcement, connecting with various regions to influence sensory responses, including nociception.

Anterior insula

A region of the insular cortex involved in processing higher-level sensory, affective and cognitive states. The anterior insula is implicated in integrating emotional responses, including those related to pain.

Central sensitization

Central sensitization is a phenomenon characterized by increased responsiveness of nociceptive neurons in the central nervous system to their normal or subthreshold afferent input.

Cingulate cortex

Located in the medial region of the cerebral cortex, wrapping around the corpus callosum, the cingulate cortex is involved in pain perception, emotion regulation, decision making and attention. The cingulate cortex integrates emotional, sensory and cognitive information and is divided into anterior and posterior sections with distinct roles in emotional processing and sensory integration.

Corticolimbic system

A neural network that expands upon the mesolimbic system to include cortical projections of the nucleus accumbens, incorporating regions such as the ventromedial prefrontal cortex, hippocampus and amygdala. The corticolimbic system has a role in emotional regulation and reward processing.

Dorsal horn

The sensory processing area of the spinal cord that receives input from peripheral nerves on pain, pressure and other stimuli, and transmits these signals to the brain.

Dorsolateral prefrontal cortex

A region of the prefrontal cortex involved in executive functions such as working memory, decision making and cognitive flexibility, often implicated in the cognitive modulation of pain.

Grey matter density

The concentration of neuronal cell bodies, dendrites and glial cells in a specific brain region. Higher density indicates greater numbers of neurons or synapses, often associated with neuroplasticity in response to experiences or injuries.

Hippocampus

A structure within the limbic system involved in memory formation and spatial navigation. The hippocampus interacts with regions involved in emotional processing, including the amygdala, and has a role in contextual memory associated with pain experiences.

Hypothalamus

Located near the pituitary gland, the hypothalamus regulates essential physiological processes such as body temperature, hunger, sleep and circadian rhythms. The hypothalamus coordinates stress responses and links the nervous system to the endocrine system through its control over the pituitary gland.

Mesolimbic system

A neural pathway implicated in reward, salience and conditioned learning, comprising key structures of the dopamine system, including the ventral tegmental area and the nucleus accumbens.

Motor homunculus

A somatotopic representation of the body in the brain’s primary motor cortex, where different body parts are controlled by specific regions along the cortex’s dorsal–ventral axis.

Negative affect

A broad psychological construct encompassing emotional distress and unpleasant feelings. It encapsulates affective dimensions such as depression, anxiety, fear and anger, frequently co-occurring with acute and chronic pain.

Nociceptors

Specialized peripheral neurons that detect noxious (painful) stimuli and transmit this information to higher-order structures in the central nervous system.

Nucleus accumbens

Part of the brain’s reward circuitry within the basal ganglia, involved in processing reward, motivation and pleasure. The nucleus accumbens has a role in reinforcing behaviours associated with pain relief.

Periaqueductal grey area

(PAG). A midbrain region involved in pain modulation, defensive behaviours and autonomic functions. The PAG integrates sensory information related to pain and, through connections with the rostroventral medulla, can inhibit pain signals in the spinal cord.

Posterior insula

A part of the insular cortex located within the brain’s lateral sulcus. The posterior insula processes sensory information related to the body’s internal state, such as nociception, temperature and visceral sensations, contributing to physical sensation perception.

Primary and secondary sensory cortices

Located in the parietal cortex, this region is essential for processing sensory information from the body, including touch, pressure, pain and proprioception. Sensory cortices receive input from the thalamus.

Primary motor cortex

The primary motor cortex is a region of the cerebral cortex located in the frontal lobe, specifically on the precentral gyrus and anterior paracentral lobule. It is the main area responsible for initiating and controlling voluntary movements.

Quantitative sensory testing

A standardized psychophysical method used to assess somatosensory function. Quantitative sensory testing helps to characterize both peripheral and central nervous system function through the application of calibrated stimuli and subsequent evaluation of various sensory modalities, including thermal, mechanical sensation and pain, and vibration sensation.

Rostroventral medulla

(RVM). A brainstem area involved in descending pain modulation, controlling the transmission of pain signals between the brain and spinal cord. The RVM can either inhibit or enhance pain signals through its connections with the dorsal horn.

Spinal sensitization

A process involving structural and functional changes in the spinal cord that amplify pain signals. Prolonged nociceptor activation leads to increased excitatory signalling and reduced inhibition, causing heightened pain sensitivity and persistent pain perception.

Spinothalamic pathway

A major ascending pathway that originates in the dorsal horn of the spinal cord and projects to the thalamus, carrying sensory information, including pain, to the brain.

Spontaneous neural activity

Ongoing, intrinsic fluctuations in neuronal firing that occur independently of explicit tasks or stimuli, representing baseline brain function. In functional magnetic resonance imaging, these are predominantly low-frequency (<0.1 Hz) fluctuations in the blood oxygen level-dependent signal captured with the MRI protocol, reflecting underlying neural processes and their associated metabolic demands.

Thalamus

A brain structure that acts as a relay centre for incoming sensory information, including pain. The lateral thalamus primarily projects to sensory brain areas, whereas the medial thalamus projects to regions involved in emotional and cognitive responses to pain.

Ventromedial prefrontal cortex

(vmPFC). A region in the lower middle part of the prefrontal cortex that is involved in decision making and emotional regulation by integrating emotional and value-based information, especially related to risk, reward and guiding behaviour.

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Barroso, J., Branco, P. & Apkarian, A.V. The causal role of brain circuits in osteoarthritis pain. Nat Rev Rheumatol 21, 261–274 (2025). https://doi.org/10.1038/s41584-025-01234-9

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