Neuropathic pain, caused by injury or disease of the somatosensory nervous system, is a major clinical challenge and often evolves into a chronic condition. Importantly, up to 80% of patients with long-term pain also experience anxiety or depression. This creates a vicious cycle that not only worsens prognosis and quality of life but also poses significant challenges for treating both the pain and the accompanying emotional disorders. Current treatments mainly focus on pain intensity, while emotional symptoms often remain inadequately addressed.
Acupuncture, an ancient Chinese practice, is now widely recognized and integrated into global pain management. It offers a drug-free option for conditions such as chronic back pain, migraines, and arthritis. High-quality clinical trials have further confirmed its efficacy in treating both acute and chronic pain. Beyond pain relief, acupuncture also demonstrates certain advantages in managing pain-induced negative emotions. While research on the potential mechanisms of acupuncture analgesia has achieved notable progress, the neural mechanisms underlying the link between acupuncture and pain-related emotional disturbances remain poorly understood.
Previous studies have indicated that the prefrontal cortex plays a critical role in integrating pain perception and emotional regulation, yet it remains unclear whether acupuncture exerts its effects by modulating the prefrontal cortex. Given these challenges, there is a pressing need to investigate whether and how acupuncture intervention influences the prefrontal cortex and modulates specific neuronal circuits, thereby alleviating pain-induced emotional disturbances.
Researchers from Shaanxi University of Chinese Medicine reported (DOI: 10.13702/j.1000-0607.20230755) in January 2025 in Acupuncture Research hat electroacupuncture significantly alleviated pain-induced anxiety- and depression-like behaviors in a mouse model of neuropathic pain by modulating specific excitatory neurons in the brain. By combining behavioral testing with chemogenetic manipulation, the team demonstrated that the therapeutic effects of electroacupuncture depend on the activation of glutamatergic neurons in the ventrolateral orbital cortex, a subregion of the prefrontal cortex closely linked to emotional processing. The study provides direct neural evidence connecting acupuncture-based intervention with brain circuit modulation.
To explore the neural basis of pain-related emotional disorders, the researchers established a neuropathic pain model in mice using common peroneal nerve ligation. A battery of behavioral tests—including open field, elevated plus maze, forced swimming, and tail suspension assays—revealed that nerve injury induced persistent anxiety- and depression-like behaviors alongside heightened pain sensitivity. Electroacupuncture was then applied daily for seven days at specific hindlimb acupoints (“Yanglingquan” (GV34) and “Xuanzhong” (GB34)) commonly used in pain treatment.
Results showed that electroacupuncture markedly improved emotional behaviors without affecting overall locomotion, indicating a genuine anxiolytic and antidepressant effect rather than a motor artifact. To uncover the underlying mechanism, the team selectively activated or inhibited glutamatergic neurons in the ventrolateral orbital cortex using chemogenetic tools. Artificial activation of these neurons mimicked the emotional benefits of electroacupuncture, while their inhibition completely blocked the therapeutic effect of electroacupuncture.
Immunofluorescence analysis further confirmed increased neuronal activation following electroacupuncture, demonstrating that excitatory prefrontal neurons are a critical neural substrate linking pain relief and emotional regulation.
“Chronic pain is not merely a sensory experience—it fundamentally alters emotional brain circuits,” said one of the study’s senior authors. “Our findings show that electroacupuncture can directly engage prefrontal glutamatergic neurons that are suppressed by long-term neuropathic pain. By restoring the activity of this circuit, emotional symptoms such as anxiety and depression can be alleviated. This provides a biological explanation for the clinical observation that acupuncture improves both pain and mood, and highlights its potential as a complementary strategy for treating complex pain-related disorders.”
These results have important implications for the treatment of chronic pain conditions complicated by emotional disorders. By identifying a specific prefrontal neural circuit involved in pain-induced anxiety and depression, the study opens new avenues for precision neuromodulation therapies. Electroacupuncture, as a low-risk and non-pharmacological intervention, may help reduce reliance on antidepressants or opioids, particularly in patients with comorbid pain and mood disorders. More broadly, the findings support an integrative neuroscience framework in which traditional therapeutic techniques are evaluated and optimized through modern brain circuit analysis, potentially accelerating their translation into evidence-based clinical practice.
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