The Role of Primary Motor Cortex in Chronic Pain Treatment

Neurology Anesthesiology Medicine
Primary Motor Cortex Chronic Pain Sensory-Motor Integration Repetitive Transcranial Magnetic Stimulation Descending Inhibitory System

The Role of Primary Motor Cortex in Chronic Pain Treatment
Chronic pain is a complex multidimensional experience involving sensory, emotional, and cognitive dimensions. Although traditional analgesic and antidepressant drugs are widely used, more than 50%-60% of chronic pain patients fail to benefit from them. Therefore, finding new treatment strategies has become an urgent need. In recent years, neuromodulation techniques have gradually gained attention as an alternative therapy, among which stimulation of the primary motor cortex (M1) is considered an effective treatment. However, the specific mechanisms of M1 in chronic pain remain unclear. In particular, how nociceptive sensory inputs affect M1 activity and how correcting M1 defects can regulate pain processing are still unresolved mysteries.

This study aims to reveal the neural circuit mechanisms of M1 in chronic pain, explore the role of sensory-motor interactions in pain processing, and elucidate the mechanisms by which M1 regulates chronic pain through descending inhibitory pathways. This research not only provides new perspectives for understanding the neural mechanisms of chronic pain but also offers a potential theoretical foundation for developing new analgesic strategies.

Source of the Paper

This paper was co-authored by Fei Wang, Zhi-Cheng Tian, Hui Ding, and others, with the research team from Fourth Military Medical University and other institutions. The paper was published on June 18, 2025, in the journal Neuron, titled “A sensory-motor-sensory circuit underlies antinociception ignited by primary motor cortex in mice.” Through interdisciplinary research methods, the paper reveals the neural circuit mechanisms of M1 in chronic pain and proposes new strategies for treating chronic pain using neuromodulation techniques.

Research Process and Results

1. Research Process

a) Establishment of Chronic Pain Models

The study first established two chronic pain models in mice: a neuropathic pain model (spared nerve injury, SNI) and an inflammatory pain model (complete Freund’s adjuvant, CFA). The effectiveness of the models was confirmed through behavioral tests, such as mechanical pain threshold and thermal pain latency.

b) Electrophysiological Recording of M1 Neurons

The research team used whole-cell patch-clamp recording to examine the electrophysiological properties of M1 glutamatergic (Glu) pyramidal neurons under chronic pain conditions. The results showed that the excitability of M1Glu neurons in SNI and CFA model mice was significantly reduced, manifested as decreased action potential frequency and reduced excitatory postsynaptic currents (EPSCs).

c) Calcium Imaging to Reveal Neuronal Activity

Using calcium imaging, the research team further observed calcium signal changes in M1Glu neurons in vivo. The results showed that the calcium signals of M1Glu neurons in response to mechanical and thermal stimuli were significantly weakened in chronic pain model mice, indicating suppressed functional activity.

d) Anatomical and Functional Connectivity of the S1-M1 Microcircuit

Through viral tracing and optogenetics, the research team revealed the anatomical and functional connections between the primary somatosensory cortex (S1) and M1. The results showed that S1Glu neurons regulate M1Glu neuron activity through feedforward inhibition mediated by M1 parvalbumin (PV) interneurons.

e) Application of Repetitive Transcranial Magnetic Stimulation (rTMS)

The research team applied high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) to M1 and found that it effectively reversed the excitation-inhibition imbalance in the S1-M1 microcircuit, restoring the functional activity of M1Glu neurons and alleviating pain hypersensitivity.

2. Main Results

a) Chronic Pain Reduces Functional Activity of M1 Neurons

The results showed that the excitability of M1Glu neurons in SNI and CFA model mice was significantly reduced, manifested as decreased action potential frequency, reduced EPSCs, and weakened calcium signals. Additionally, abnormal dendritic spine remodeling was observed in M1Glu neurons, particularly a reduction in mushroom and stubby spines.

b) Excitation-Inhibition Imbalance in the S1-M1 Microcircuit

The study found that under chronic pain conditions, the activity of S1Glu neurons increased, leading to enhanced feedforward inhibition mediated by M1PV interneurons, which in turn reduced the excitability of M1Glu neurons. This excitation-inhibition imbalance is a key mechanism underlying the reduced functional activity of M1.

c) rTMS Reverses M1 Defects and Alleviates Pain

By stimulating M1 with HF-rTMS, the research team successfully reversed the excitation-inhibition imbalance in the S1-M1 microcircuit, restored the functional activity of M1Glu neurons, and significantly alleviated pain hypersensitivity in chronic pain model mice.

d) Descending Inhibitory Role of the M1-LHPV Pathway

The study also found that M1Glu neurons, by projecting to PV neurons in the lateral hypothalamus (LHPV), activated the descending inhibitory pathway mediated by the ventrolateral periaqueductal gray (vlPAG), thereby regulating spinal nociceptive inputs.

3. Conclusions and Significance

This study systematically reveals the neural circuit mechanisms of M1 in chronic pain for the first time, elucidating the critical role of sensory-motor interactions in pain processing. The results indicate that under chronic pain conditions, S1Glu neurons enhance feedforward inhibition mediated by M1PV interneurons, leading to reduced functional activity of M1Glu neurons and weakening M1’s regulatory control over descending inhibitory pathways. By stimulating M1 with HF-rTMS, this process can be effectively reversed, restoring M1’s functional activity and alleviating pain hypersensitivity.

This research not only provides new perspectives for understanding the neural mechanisms of chronic pain but also offers a potential theoretical foundation for developing new analgesic strategies. In particular, correcting M1 defects through neuromodulation techniques, such as rTMS, may become an effective approach to treating chronic pain.

4. Research Highlights

  • Key Findings: Reveals the neural circuit mechanisms of M1 in chronic pain and elucidates the critical role of sensory-motor interactions in pain processing.
  • Innovative Methods: Combines viral tracing, optogenetics, calcium imaging, and electrophysiology to systematically study the functional and structural connectivity of the S1-M1 microcircuit.
  • Application Value: Provides new neuromodulation strategies for treating chronic pain through HF-rTMS stimulation of M1.

Additional Valuable Information

This study also highlights the important role of the M1-LHPV-vlPAG pathway in chronic pain, offering new directions for further research on the neural regulation of pain. Additionally, the experimental methods and techniques developed by the research team, such as viral tracing and optogenetics, provide important tools and references for neuroscience research.

This study not only deepens our understanding of the neural mechanisms of chronic pain but also provides important theoretical foundations and technical support for developing new analgesic strategies.