Therapeutic modulation of pain-related affective disorders by acupuncture: Mechanistic review

Abstract

This review reexamines the mechanism by which acupuncture (especially electroacupuncture) modulates pain-related affective disorders from an integrative functional framework. We propose that the efficacy of acupuncture stems from its regulatory functions that mobilize and coordinate multiple internal physiological systems at the same time. Specifically, it is mainly realized through five functional modules: (1) central network remodeling function: correcting abnormal functional connections and neural circuit activity in brain regions related to pain and emotion; (2) Neuroplasticity and repair function: activate neurotrophic pathways and synaptic regulatory mechanisms to promote neural adaptation; (3) Systematic homeostasis regulation function: balancing the interaction of neurological-endocrine-gut axes; (4) Nociceptive signal gating function: a common signaling pathway that accurately inhibits pain and negative emotions at the molecular and receptor levels; (5) Neuroimmune regulatory function : targeted inhibition of central-specific inflammatory pathways and cytokine storms. This article aims to systematically summarize the evidence from the past 5 years and clarify how these five functions constitute a synergistic treatment network, providing a new perspective for the clinical application and mechanism research of acupuncture.

Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage. ¹ In clinical practice, pain is often accompanied by affective disorders such as anxiety and depression, which significantly affect the patients’ quality of life. ² Statistics show that approximately half of neuropathic pain patients develop comorbid affective disorders, and chronic pain patients face a fourfold higher risk of affective disorders than the general population. These negative emotions not only exacerbate the suffering of patients but also may hinder the progress of treatment, forming a vicious cycle between pain and affective disorders. ³ Therefore, finding effective methods to alleviate affective disorders associated with pain is of great clinical significance (see Figure 1).

Figure 1.

Figure schematic diagram of the mechanism underlying acupuncture and moxibustion in pain-related affective disorders. Acupuncture and moxibustion regulates spinal endogenous opioids, NMDA receptors, and the IL-BLA pathway by optimizing stimulation parameters, acupoints, and treatment cycles. It synergistically modulates peripheral targets (TRPV1 inhibition, reduced inflammatory factors, P2Y12 signaling) and central targets (brain network, emotion-pain integration, reward circuit). These effects enhance neural plasticity (BDNF upregulation), epigenetic modification, and microglial polarization, restoring HPA axis function, autonomic balance, and gut-brain axis homeostasis, thereby improving pain and emotional disorders.

In recent years, electroacupuncture (EA), as a modern application of traditional Chinese medicine, has attracted widespread attention due to its safety, efficacy, and minimal side effects.^4,5 A large number of clinical and animal experimental studies have shown that EA can not only effectively relieve pain but also significantly improve affective disorders such as anxiety and depression associated with pain.^6,7 For example, some studies have found that EA can improve mechanical allodynia and emotional dysfunction in mice with neuropathic pain by regulating the gut microbiota. ⁸ In addition, EA has also been proven to relieve pain-related emotions by regulating the release of various neurotransmitters in the brain and the expression of their receptors.^9,10 This paper reviews clinical and mechanistic studies on EA in alleviating affective disorders associated with pain, aiming to comprehensively summarize the research achievements in this field and explore its mechanisms of action. We employed a step-by-step methodology for literature retrieval.

Initially, we conducted a comprehensive search of the PubMed database covering the period from 2019 to 2024. Subsequently, in July 2024, we carried out a highly focused search within the PubMed database using the search terms “acupuncture” and “pain”. This targeted search was specifically designed to identify novel research emerging in this particular domain. Two authors independently conducted a meticulous screening of the titles and abstracts obtained from the database search. In case of discrepancies or differences in opinion between the two authors, a third, impartial author was consulted to resolve these issues. Importantly, the search had no restrictions on language or publication date. We hope to provide a theoretical basis for the clinical application of EA in treating affective disorders associated with pain and offer references for future in-depth mechanistic studies, thereby promoting the further development and application of EA therapy.

Central network remodeling function: Correcting abnormal brain connections and loops

Acupuncture directly remodels the brain network architecture disrupted by chronic pain by modulating the activity intensity, functional connectivity, and excitability of specific neural circuits in key brain regions, thereby restoring its normal integration and processing capacity of sensory and emotional information.

Regulate large-scale brain networks and regional functional connectivity

Functional connectivity of brain regions (fMRI) has been instrumental in revealing acupuncture’s effects on the central nervous system.^11–13 Multiple studies show that acupuncture can regulate the activity and functional connectivity (FC) of specific brain regions.^13–15

Zhang et al. ¹⁶ explored EA’s role in preventing migraines and improving emotional symptoms in MMoA patients. Using resting-state functional Magnetic Resonance Imaging (rs-fMRI), they compared true acupuncture (TA) and sham acupuncture (SA) group. Menstrual migraine without aura (MMoA) patients had lower left anterior cingulate cortex amplitude of low-frequency fluctuations (ALFF) values, correlated with reduced self-rating anxiety scale (SAS) and self-rating depression scale (SDS) scores 16. In the SA group, ALFF and regional homogeneity changes were mainly in the insula, ¹⁷ with no clinical correlations. Both treatments worked, but TA better reduced migraine frequency. TA modulated emotions via frontal-limbic regions, while SA might act through a placebo effect on the insula, supporting EA as a migraine complementary therapy.^18,19

Liu et al. ²⁰ studied EA’s effects in preventing migraines in migraine without aura (MwoA) patients. With rs-fMRI, they compared regional homogeneity (ReHo) between MwoA patients and healthy controls. MwoA patients had lower cerebellar ReHo, which increased after the first EA session. Long-term EA improved symptoms and mood for at least 6 months and increased ReHo in the cerebellum and angular gyrus after 12 sessions (acupuncture on 2 days per week for 6 weeks for a total of 12 sessions followed by 24 weeks of follow-up).^20,21 This suggests that migraine involves cerebellar dysfunction, which EA can correct this by enhancing cerebellar function and activating pain- and emotion-related brain regions.

Another study comprehensively examined EA’s efficacy in treating migraine without aura using (rs-fMRI). ²² EA significantly reduced headache-related measures and anxiety/depression scores, with a 94.1% effective rate. Before treatment, the functional connectivity (FC) between the periaqueductal gray (PAG) and the right cerebellum Ⅷ was decreased. After EA, PAG-bilateral cerebellum Ⅷ and PAG-left precuneus FC increased. ²² PAG-right cerebellum Ⅷ FC correlated negatively with VAS scores before treatment, and PAG-left precuneus FC correlated positively with headache improvement, suggesting EA’s therapeutic effects on abnormal brain regions.

Functional gastrointestinal disorders (FGIDs), related to brain-gut interaction disorders, can be treated with EA, which improves symptoms and emotional states.^23,24 Wang et al. ¹³ evaluated 10 randomized controlled trials (RCTs) with fMRI data. EA improved gastrointestinal and psychological symptoms and regulated brain functional connections in regions like the insula and amygdala. The COVID-19 epidemic increased student anxiety. ²⁵ Clinically, acupuncture at LU10 (Yuji) can relieve anxiety by regulating Qi. ²⁶ In an experiment, the LU10 (Yuji) and non-acupoint groups received EA during functional magnetic imaging. ¹⁵ After acupuncture, LU10 activated left-brain regions like the frontal lobe compared to the control group. Acupuncture at LU10 also increased FC in several regions and had specific FC changes in the hippocampus and other areas, indicating that EA at LU10 can regulate anxiety by modulating relevant brain regions and connections, and LU10 can treat both lung and mental disorders. ¹⁵

Migraine, a highly prevalent and disabling neurological disorder, often shows limited response to pharmacotherapies with frequent adverse effects.^27,28 EA, a promising complementary therapy, lacks sufficient clinical evidence and mechanistic understanding. ²⁹ A randomized controlled trial investigated acupuncture in 38 migraineurs and 10 controls. ³⁰ Migraineurs were divided into groups and received two 5-day treatment courses. Analyses showed acupuncture alleviated symptoms, modulated brain regions and signaling pathways. Metabolite/protein changes may precede brain effects, indicating a complex therapeutic mechanism. However, more high-quality studies are needed.

Regulate the activity of the brain’s reward circuits

The relief of chronic pain acts as negative reinforcement by activating the brain’s reward circuits, which participate in both reward processing and pain modulation, ³¹ but acupuncture’s reward effects in chronic pain and the role of these circuits in acupuncture analgesia are not well understood. Liu et al. ³² discussed the significance of researching EA analgesia’s reward effect and related brain reward circuits. They proposed ideas and determined EA analgesia’s characteristics, and focusing on these aspects could deepen our understanding of acupuncture mechanisms. ³²

Atopic dermatitis (AD), often accompanied by anxiety and depression,^33,34 can be treated with EA, which may also relieve these comorbidities.^35–38 In a mouse model, EA at LI11 (Quchi) reduced AD-like symptoms and improved anxiety- and depression-like behaviors. ³⁹ EA reversed changes in brain reward regions, and striatal ΔFosB levels correlated with reduced scratching and distress, suggesting EA modulates brain reward circuitry to improve AD-related mental health.^39,40

Neural circuits of relevant brain regions

Acupuncture also shows potential in treating visceral pain and neck pain. Regarding visceral pain, it integrates signals from acupoints and pain sites within the central nervous system, modulating key brain nuclei and neural circuits. ⁴¹

Wang et al. ⁴² explored the impact of acupuncture on chronic neck pain. In a study involving 99 patients, those receiving true acupuncture showed significant improvements in pain intensity and attack duration. Brain imaging revealed that true acupuncture enhanced functional connectivity within the serotonergic system and related neural circuits. ⁴¹

Moreover, acupuncture has been found to treat various diseases, including gastrointestinal and cardiovascular disorders, as well as mental health issues like anxiety and depression, by modulating the paraventricular hypothalamic nucleus (PVN). ⁴³ It influences specific neurons in the PVN, such as corticotropin-releasing hormone neurons, and regulates hormone release and associated neural circuits.

In conclusion, acupuncture exerts diverse therapeutic effects related to the autonomic nervous system (ANS) and neural circuits in pain and mental health conditions.^41,42,44 Future research should focus on uncovering the underlying mechanisms, especially how acupoint stimulation affects organs through central nervous networks and efferent autonomic nervous system (ANS) pathways. This will enhance our understanding and optimize the therapeutic potential of acupuncture.

Neural plasticity and repair function: Promoting synaptic remodeling and neural adaptation

Acupuncture enhances the structural and functional plasticity of the nervous system by upregulating key neurotrophic factors, modulating the expression of synapse-related proteins, and inducing epigenetic modifications, thereby providing a cellular and molecular basis for the long-term alleviation of pain and emotional disorders.

Activation of brain-derived neurotrophic factor and its downstream signaling pathways

Chronic inflammatory pain (CIP) often accompanies depression, with both conditions linked to altered synaptic plasticity. EA has been shown to relieve CIP and depression, although the mechanisms remain unclear. ⁴⁵ Yang et al. ⁴⁶ investigated whether EA alleviates CIP and depression by modulating hippocampal synaptic plasticity, providing evidence for its efficacy in treating CIP-related depression (CIPD). EA mitigated pain and depressive behaviors, protected hippocampal neurons, and regulated 5-HT/GABA/Glu levels. It also increased synaptic protein expression (e.g. PSD-95 and Syn) by activating the brain-derived neurotrophic factor (BDNF)/TrkB/cAMP-response element-binding protein (CREB) pathway. Thus, EA’s therapeutic effects on CIPD may involve synaptic plasticity mediated by the BDNF/TrkB/CREB pathway.

Diabetes and depression often co-occur, creating a significant health burden. EA may alleviate symptoms in these patients, but its mechanisms are unclear. BDNF is thought to play a key role, potentially acting through the BDNF-TrkB-ERK-CREB pathway. Reduced BDNF levels in diabetes and depression may be increased by acupuncture, improving symptoms and glycemic control. ⁴⁷ Further high-quality research, including randomized controlled trials and mechanistic studies, is needed to confirm acupuncture’s efficacy and explore the BDNF pathway and other mechanisms. Understanding these links could enable personalized care and improve early diagnosis and management of this comorbidity.

GV20 (Baihui) and DU29 (Yintang) are key acupuncture points for treating depression. Yamamoto et al. ⁴⁸ compared the antidepressant effects of manual acupuncture (MA) stimulation at GV20 and DU29, compared to acupuncture stimulation at two control point locations on the back of the mice (over the spinal column) and imipramine administration in a forced swimming (FS)-induced mouse model of depression, and examined the mRNA and protein expression of neurotrophic factors. This study found that simultaneous stimulation at these points significantly reduced immobility time in mice with depression, comparable to the antidepressant imipramine. In preventive and therapeutic experiments, acupuncture at GV20 and Yintang outperformed control points, increasing expression of neurotrophic factors like BDNF, nerve growth factor (NGF), and neurotrophin (NT)-3/4/5. These results suggest that acupuncture at GV20 and Yintang effectively prevents and treats depression by modulating multiple neurotrophic factors.

Su et al. ⁴⁹ have previously found that EA has a good analgesic effect on cervical spondylotic radiculopathy (CSR). However, the central analgesic mechanism of EA for CSR is not yet clear. In the experiment, the rats were randomly divided into Blank group, Sham-operated group, CSR group, and EA group. ⁴⁹ Central sensitization is a key mechanism in neuropathic and radicular pain from CSR. The CaMKII/CREB/BDNF pathway mediates central sensitization via spinal cord synaptic plasticity. EA has shown analgesic effects in CSR rats by improving pain thresholds and motor function, and reducing BDNF, P-TrkB, CaMKII, P-CREB, c-Fos, and neuroligin-2 expression in spinal cord synapses. ⁵⁰ EA modulates spinal synaptic plasticity and suppresses overactive synaptic efficacy, likely through inhibiting the CaMKII/CREB/BDNF pathway, thereby alleviating central sensitization and pain in CSR. ⁵¹

Cong et al. ⁵² explored the analgesic and antidepressant effects of EA on chronic neuropathic pain. EA increased mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values, improved depression-like behaviors induced by chronic constriction injury (CCI), and reversed the downregulation of BDNF and 5-hydroxytryptamine (5-HT) in the anterior cingulate cortex (ACC) and spinal cord. ⁵³ EA also regulated CREB levels in these regions. These results suggested that the analgesic and antidepressant effect of EA is achieved through regulating CREB-5-HT/BDNF signaling pathway in the ACC and spinal cords of mice. ⁵²

EA also regulates pain-related emotions by modulating the gut microbiota. Depression and chronic pain are linked to abnormal gut microbiota. Li et al. ⁵⁴ showed that EA reduced pain and depression-like behaviors, modulated gut microbiota, and increased short-chain fatty acids (SCFAs)-producing bacteria, particularly Akkermansia. EA also increased BDNF and acetylated Histone H3 (AcH3) while decreasing histone deacetylase 2 (HDAC2) in the mPFC, with SCFAs-producing bacteria correlating negatively with HDAC2 levels. Thus, EA’s therapeutic effects may involve gut microbiota modulation, histone acetylation changes, and BDNF upregulation. ⁴⁵

Mediate epigenetic regulation and the gut-brain axis dialogue

Depression and chronic pain frequently co-occur, exacerbating each other’s symptoms and hindering treatment. Emerging studies have highlighted abnormal gut microbiota in both conditions. Previous studies have demonstrated the clinical effectiveness of EA in managing these conditions, yet the underlying mechanisms remain elusive. EA treatment significantly ameliorated pain and depression-like behavior. ⁵⁴ The 16S rDNA sequencing showed EA modulated gut microbiota composition, increased short-chain fatty acids (SCFAs)-producing bacteria, including Akkermansia, Ruminococcaceae, and Lachnospiraceae family, particularly Akkermansia . ⁵⁵ Furthermore, EA increased BDNF, AcH3 and decreased HDAC2 in mPFC. Notably, SCFAs-producing bacteria exhibited a negative correlation with HDAC2 levels. The therapeutic effects of EA on the comorbidity of chronic pain and depression may involve the modulation of the gut microbiota, resulting in histone acetylation changes and upregulation of BDNF. ⁴¹

Anxiety and depressive disorders may disrupt the dynamic bidirectional communication system within the microbiota-gut-brain (MGB) axis involving immunological, metabolic, and neurological pathways, potentially mediating alterations in gut microbial diversity and community composition. A study utilizing EA treatment at ST36 (Zusanli) and SP6 (Sanyinjiao) acupoints in a 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis rat model, combined with 16S rDNA amplicon sequencing to assess gut microbiota, found that EA treatment significantly alleviated TNBS-induced anxiety-depression-like behaviors while downregulating hypothalamic-pituitary-adrenal (HPA) axis activity. ⁵⁶ In post-stroke pain models, acupuncture treatment significantly alleviated pain behaviors while suppressing the Sirtuin 1 (SIRT1)/NOD-like receptor thermal protein domain-associated protein 3 (NLRP3)/interleukin-18 (IL-18) signaling pathway. ⁵⁷ In post-stroke depression (PSD) rats, acupuncture treatment at GV20 (Baihui), GV24 (Shenting), and bilateral ST36 (Zusanli) acupoints improved anxiety-depression-like behaviors. Combined with 16S rRNA sequencing analysis of gut microbiota, the study revealed that acupuncture treatment increased microbial diversity. ⁵⁸ These studies demonstrate that the gut-brain axis serves as a critical regulatory target for acupuncture treatment in managing depression comorbid with pain.

Systemic homeostatic regulation function: Balancing the neuroendocrine-gut axis

Acupuncture acts on the higher integrative system that maintains the overall homeostasis of the organism, improving the emotional and visceral dysfunction associated with pain at the systemic level by regulating the stress hormone axis, autonomic nervous tension, and gut microbiota.

Regulate the hypothalamic-pituitary-adrenal axis

Liu et al. ⁵⁹ explored the mechanism of EA-induced cumulative analgesic effects on chronic pain in rats with or without ovariectomy (OVX). The paw withdrawal latency (PWL, pain threshold) of the bilateral footplates was detected by radiant heat irradiation, and the bilateral difference in PWL (PWLD) was used to evaluate changes in the pain reaction. In simple CCI rats, both β-endorphin (ED) and adrenocorticotropic hormone (ACTH) contents of the pituitary increased markedly, and those of the hypothalamus decreased obviously compared to the normal control group. After EA, pituitary and hypothalamic ACTH levels were significantly lowered at 2 days (2d) and hypothalamic ACTH and β-ED contents increased obviously at 3 weeks (3W) in comparison with the CCI group. ⁴⁵ In OVX+CCI rats, following EA, pituitary β-ED contents at 2d, 2W and 3W, and hypothalamic β-ED and ACTH contents at 2W and hypothalamic ACTH levels at 3W increased significantly, but hypothalamic β-ED level at 3W decreased markedly. The effects of repeated EA in lowering pituitary ACTH and raising hypothalamic β-ED and ACTH levels disappeared after OVX+CCI. Therefore, repeated EA has a cumulative analgesic effect, which is closely associated with its effects in regulating pituitary and hypothalamic β-ED and ACTH levels. ⁶⁰ OVX may weaken the analgesic effect of EA by affecting hypothalamic-pituitary axis activity.

Regulate the balance of the autonomic nervous system

The ANS, comprising the sympathetic, parasympathetic, and enteric nervous systems, is crucial for maintaining physiological homeostasis. ⁶¹ Emerging research indicates that the ANS serves as a pivotal pathway for acupuncture signal transduction.^62,63 Over the past two decades, Li et al. ⁴⁴ have demonstrated that acupuncture effectively mitigates symptoms associated with ANS dysfunction, such as migraine, depression, and functional dyspepsia. By stimulating specific acupoints, acupuncture activates sensory nerves and key brain regions like the insular cortex and hypothalamus. This, in turn, modulates autonomic nerves to reduce visceral dysfunction and pain. ⁴⁴ However, achieving the optimal balance between sympathetic and parasympathetic activities during acupuncture requires further investigation.

Harmful signaling gatekeeping function: Inhibition of key molecules and receptor pathways

Acupuncture establishes “gateways” on the molecular signaling pathways of pain and emotional sharing, directly attenuating the transmission of nociceptive information and negative emotional processing by modulating specific ion channels, neurotransmitter receptors, and their downstream signals.

Inhibition of TRPV1 channel-mediated signaling

Chronic pain, defined as lasting over 3 months, is a significant health problem that can impair daily activities and lead to psychological issues, often associated with conditions such as fibromyalgia (FM) and accompanied by anxiety, sleep disturbances, and obesity. Central sensitization due to imbalanced neurotransmission is common in chronic pain patients, with TRPV1, an ion channel detecting inflammation, playing a key role in transmitting pain signals. The study investigated the effects of acupoint catgut embedding (ACE) on cold stress-induced FM in mice and the role of TRPV1. ⁶⁴ Behavioral experiments demonstrated that ACE treatment and TRPV1 gene deletion (Trpv1^−/−) alleviated mechanical and thermal pain in FM mice. Inflammatory mediators and TRPV1-related kinases were elevated in FM but were reduced by ACE or TRPV1 inhibition. ¹⁰ These findings suggest that targeting TRPV1 signaling through ACE or TRPV1 modulation could be effective therapeutic strategies for FM treatment.

Chronic pain and depression share overlapping clinical and pathological features, including neuroinflammation, which can be reversed by EA. TRPV1, a Ca²⁺-permeable ion channel involved in chronic pain and depression, was studied by Liao et al. ⁴⁵ in a mouse model using Complete Freund’s adjuvant (CFA). They measured inflammatory mediators and evaluated TRPV1 signaling in the mPFC, hypothalamus, and PAG. EA and TRPV1 deletion attenuated CFA-induced inflammation and improved pain and depression measures. This study highlights TRPV1 as a potential therapeutic target for both conditions. ⁶⁵

Lin et al. ⁴⁵ studied TRPV1’s role in cold stress-induced chronic pain and depression in female C57BL/6 wild-type and TRPV1 knockout mice. Intermittent cold stress (ICS) induced chronic pain and depressive-like behaviors. EA, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) treatments improved these behaviors and reversed increased inflammatory mediators. TRPV1 and related molecules were decreased in the mPFC, hippocampus, and PAG but increased in the amygdala, with the effects being reversed by EA, DHA, and EPA. These findings suggest that targeting TRPV1 and inflammatory mediators could be a potential therapeutic strategy for chronic pain and depression.

Regulate the release of endogenous opioid peptides

Li et al. ⁶⁶ examined auricular point sticking therapy for pain management in patients undergoing partial lung resection. The therapy significantly reduced visual analogue scale (VAS) pain scores compared to sham and medication groups at multiple time points and achieved faster pain relief. Hospital anxiety and depression scale (HADS) scores for anxiety and depression were also lower in the auricular point group at 8 and 72 h. Plasma β-endorphin levels were higher at 24 and 48 h, indicating a potential analgesic mechanism. The therapy also had fewer adverse reactions. Thus, auricular point sticking therapy effectively alleviates postoperative pain and improves mood, likely through increased β-endorphin levels. ⁶⁰

Acupuncture is thought to activate the body’s pain-relief system, often linked to β-endorphin and opioid receptors. However, beta-endorphin release is stress-induced and not necessarily analgesic. Harbach et al. ⁶⁷ examined whether acupuncture releases beta-endorphin into the bloodstream under low-stress conditions. Fifteen male patients with chronic low back pain underwent standard pain treatment, traditional acupuncture, sham acupuncture, EA, and EA at non-acupuncture points. Plasma cortisol and beta-endorphin levels were measured before, during, and after treatments. Cortisol levels decreased significantly across all treatments, but beta-endorphin levels remained minimal and unchanged. ⁵⁰ No significant differences were found between treatments. The results suggest acupuncture does not significantly release beta-endorphin under low-stress conditions. ⁴⁵

Inhibition of N-methyl-D-aspartate receptors (NMDARs) and related kinase signaling

Yuan et al. ⁶⁸ observed the effects of EA on the expression levels of N-methyl-D-aspartate receptor (NMDAR), extracellular signal-regulated kinase (ERK)1/2, p38 mitogen activated protein kinase (p38 MAPK) and c-Jun N-terminal kinase (JNK) in the spinal cord of rats with primary dysmenorrhea (PDM), so as to explore the underlying mechanism of EA treating PDM. Compared with the normal group, the writhing times and writhing score were significantly increased; the endometrial epithelial cells showed vacuolar degeneration, death and hyperemia, the uterine pathological score was increased; the content of serum PGF2α and the ratio of PGF2α/PGE2 were significantly increased, while the content of serum PGE2 was significantly decreased; the expression levels of NMDAR, ERK1/2, p38MAPK and JNK in spinal cord were significantly increased in the model group. EA intervention at ST36 (Zusanli) and GV4 (Mingmen) has obvious analgesic effect on PDM rats, and its mechanisms may be related to reducing serum prostaglandin, alleviating uterine inflammation, and inhibiting the protein expressions of NMDAR, ERK1/2, p38 MAPK and JNK in spinal cord. ⁶⁹

Acupoint catgut embedding (ACE) is a traditional Chinese medicine technique used to treat chronic inflammatory pain. This study compared ACE’s analgesic effects with EA in a rat model of inflammatory pain induced by CFA. ACE administered weekly at ipsilateral ST36 (Zusanli) and GB30 (Huantiao) acupoints was most effective, comparable to EA at the same acupoints. ⁷⁰ ACE reduced pain by inhibiting GluN1 subunit activation and downstream Ca²⁺-dependent signaling (CaMKII, ERK, CREB), similar to the 5-HT₁AR agonist vilazodone, and was blocked by the 5-HT₁AR antagonist WAY-100635. ⁷¹ These findings suggest ACE alleviates inflammatory pain by activating spinal 5-HT₁AR and suppressing GluN1 phosphorylation, offering insights into its molecular mechanisms and clinical potential. ⁷²

Modulate the IL-BLA pathway

Animal experiments also show EA alleviates pain-related mood disorders by modulating neural circuits.^73,74 The infralimbic amygdala (IL) and basolateral amygdala (BLA) are linked to negative emotions and pain, with reciprocal connections.^75–77 Xie et al. ¹⁴ used chemogenetic tools to study pain-induced depression-like behaviors. Activating the IL CaMKIIα⁺-BLA circuit induced depression-like behavior in mice and blocked EA’s antidepressant effects. Inhibiting the circuit mitigated depression-like behaviors, like EA, but not anxiety-like behaviors, suggesting the IL-BLA circuit selectively regulates pain-induced depression-like behaviors.

Chronic pain often occurs with mental health problems, and there are sex differences in this comorbidity.^78,79 For example, neuropathic pain can trigger anxiety and depression. The IL-BLA circuit in the brain is involved in this process. Xie et al. ¹⁴ conducted research on mice with spared nerve injury. They found that chemogenetic activation of the IL-BLA circuit led to depression-like behavior and blocked the antidepressant effects of EA. ¹⁴ Conversely, inhibiting this circuit or applying EA alleviated SNI-induced depression-like behavior. This suggests that the IL-BLA circuit could be a potential therapeutic target for pain-depression comorbidities.

Neuroimmune regulatory function: Inhibition of central-specific inflammation

Acupuncture selectively inhibits the excessive activation of immune cells and the production of pro-inflammatory factors in the central nervous system, thereby breaking the vicious cycle between neural inflammation and pain-emotional disorders.

Inhibition of the TLR4/NF-κB core inflammatory axis

The Toll-like receptor 4 (TLR4) pathway serves as a critical mediator of neuroinflammation in pain-emotion comorbidities. In fibromyalgia (FM) models, elevated TLR4 expression in the hypothalamus, PAG, and cerebellum is closely associated with chronic pain and psychiatric symptoms such as depression and sleep disturbances. EA effectively suppressed TLR4 and downstream inflammatory mediators (e.g. nuclear factor (NF)-κB, IL-1β) in FM mice, whereas sham acupuncture showed no significant effects. ⁸⁰ Notably, TLR4 activation via lipopolysaccharide (LPS) exacerbated FM-related hyperalgesia and anxiety-like behaviors, both of which were reversed by EA or pharmacological TLR4 antagonism. ⁸¹ These findings underscore EA’s specificity in modulating TLR4-driven inflammatory cascades.

In poststroke depression (PSD) models, EA at ST36 (Zusanli) attenuated hippocampal TLR4/p38/NF-κB/NLRP3 signaling, reduced pro-inflammatory cytokines, such as IL-1β, IL-6, TNF-α, and promoted neurogenesis in the dentate gyrus. ⁸² Transcriptomic analysis further revealed that EA normalized TLR4/NF-κB axis activity, linking its antidepressant effects to hippocampal immune homeostasis. ⁸³ Similar mechanisms were observed in chemotherapy-induced neuropathy: EA alleviated paclitaxel-related mechanical hypersensitivity by downregulating TLR4-TRPV1 crosstalk in dorsal root ganglia (DRGs) and inhibiting spinal microglial activation. ⁶ Pharmacological blockade of TRPV1 replicated EA’s analgesic effects, while TRPV1 agonists reversed these benefits, highlighting TLR4 as a therapeutic nexus for neuropathic pain.

In chronic constriction injury (CCI) models, EA suppressed spinal TLR4/MyD88 signaling and IL-1β release, correlating with improved mechanical thresholds and reduced depressive behaviors. ⁸⁴ A meta-analysis of 12 randomized controlled trials (RCTs) demonstrated EA’s efficacy in reducing TLR4-mediated neuroinflammation across diverse pain conditions (e.g. osteoarthritis, migraine), with pooled effect sizes favoring EA over sham interventions. ⁸⁵

Downregulation of key pro-inflammatory cytokines

Pro-inflammatory cytokines, particularly TNF-α and IL-6, act as molecular bridges between chronic pain and depression. In a rat model of comorbid chronic somatic pain and depression, EA at ST36 suppressed TNF-α overexpression in the prefrontal cortex (PFC), hippocampus, and amygdala, paralleling improvements in pain thresholds and depressive behaviors. ⁸⁶ Transcutaneous auricular vagus nerve stimulation (taVNS), a non-invasive EA variant, similarly reduced TNF-α levels in plasma and brain regions, suggesting shared anti-inflammatory pathways. ⁸⁷

Contrary to initial hypotheses, a clinical trial comparing pain-specific (e.g. LI4 (Hegu)) and depression-specific (e.g. GV20) acupoints found no significant differences in IL-6 or TNF-α modulation among patients with major depressive disorder and chronic pain. Both interventions equally alleviated symptoms, implying overlapping cytokine-mediated mechanisms. ⁸⁸ Preclinical studies further support this observation: EA reversed chronic unpredictable mild stress (CUMS)-induced hippocampal IL-1β elevation in depression models, while TLR4/MyD88 pathway inhibition mimicked EA’s effects on microglial quiescence. ⁸⁹

In diabetic depression models, EA enhanced hippocampal BDNF expression, counteracting TNF-α-induced synaptic plasticity deficits 52. Spinal nerve ligation (SNL) rats treated with EA exhibited reduced IL-1β/IL-18 levels via NLRP3 inflammasome suppression, improving both nociception and anxiety-like behaviors. ⁹⁰

Target purinergic P2Y12 receptor signaling

The P2Y purinoceptor 12 (P2Y12) receptor, involved in platelet aggregation, is implicated in brain IL-1β expression linked to depression. Its role in mediating comorbid visceral pain and depression in IBD via the mPFC remains unclear. Li et al. ⁹¹ investigated whether EA treats IBD by targeting P2Y12 in the mPFC. It was found that IBD mice exhibited increased mPFC P2Y12 expression associated with visceral pain and depression, which was attenuated by P2Y12 shRNA and EA. ⁹² Both interventions downregulated P2Y12, inhibited microglial activation, and reduced IL-1β expression in the mPFC. This study suggests that targeting mPFC P2Y12 with EA could be a novel therapeutic approach for comorbid visceral pain and depression in IBD, potentially expanding EA’s clinical applications. ⁹³

EA alleviates arthritis-induced pain by inhibiting spinal microglial activation, a key factor in pain hypersensitivity. Wang et al. ⁹⁴ explored EA’s mechanism in monoarthritis rats induced by CFA. EA at GB30 (Huantiao) and GB34 (Yanglinquan) acupoints reduced pain and spinal microglia M1 polarization. Monoarthritis increased the expression of the P2Y12 receptor (P2Y12R) in the spinal dorsal horn, which was suppressed by EA. ⁹¹ P2Y12R was primarily expressed in microglia. Pharmacological inhibition of P2Y12R with AR-C69931MX reduced microglial activation and enhanced EA’s pain-relieving effects. These findings show EA alleviates MA-induced pain by inhibiting P2Y12R-dependent microglial activation. ⁹²

Conclusion

Acupuncture effectively relieves pain and related affective disorders through multidimensional mechanisms, forming a “brain-nerve-immune” integrated regulatory network. At the structural level of brain regions, fMRI studies have confirmed that acupuncture can remodel the functional connections of brain regions related to pain and emotion (such as the prefrontal cortex, insular lobes, and thalamus), activate the default mode network and salience network, enhance the reward effect through the mesolimbic dopaminergic system, regulate the interaction between metabolic homeostasis and the brain-gut axis, and improve visceral pain and anxiety. At the neurotransmitter level, acupuncture achieves multi-level analgesia and emotion regulation by promoting endorphin release, inhibiting TRPV1 and NMDARs-mediated pain sensitization, enhancing BDNF-driven neuroplasticity, and blocking P2Y12 receptor-related neuroinflammation. At the level of immune regulation, acupuncture balances the immune microenvironment and blocks the vicious cycle of “pain-inflammation” by inhibiting the TLR4/NF-κB pathway and downregulating the expression of pro-inflammatory factors (such as IL-1β and TNF-α). Together, these mechanisms reveal the comprehensive intervention characteristics of acupuncture and moxibustion that integrate neuroplasticity, molecular signaling, and immune homeostasis.

Prospect

Future research needs to further address the following questions:

1. In-depth mechanism analysis: Existing studies focus on a single pathway, and it is necessary to combine multi-omics techniques (such as spatial transcriptome and single-cell sequencing) to reveal the dynamic interaction of brain region-nerve-immune network.

2. Clinical translational validation: Most of the evidence comes from animal models, and it is necessary to determine the impact of acupuncture parameters (such as acupuncture point specificity and stimulation frequency) on clinical efficacy through large-sample randomized controlled trials;

3. Individualized treatment strategy: explore the association between gene polymorphisms (e.g. Val66Met of BDNF), intestinal microbiota characteristics and acupuncture response, and promote the application of precision medicine;

4. Interdisciplinary technology integration: Combined with brain-computer interface and real-time monitoring of neuroimaging, dynamic analysis of the spatio-temporal effects of acupuncture intervention;

5. Combination therapy development: To explore the synergistic mechanism of acupuncture and pharmacological and psychological interventions to optimize the treatment of chronic pain and comorbid mood disorders.

In summary, acupuncture, as a “multi-target-multi-system” regulatory tool, is expected to provide a new intervention paradigm for pain-emotion comorbidity, but its system biological mechanism and clinical value still need to be explored through interdisciplinary collaboration.