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Background: Insufficiently managed incisional (INC) pain severely affects patients' life quality and rehabilitation after a major operation. However, mechanisms underlying INC pain still remain poorly understood. Methods: A mouse model of INC pain was established by skin plus deep muscle incision. Biochemistry assay, in vivo reactive oxygen species (ROS) imaging, Ca2+ imaging combined with retrograde labelling, neuron tracing and nocifensive behavior test, etc. were utilized for mechanism investigation. Results: We found pro-nociceptive cytokine interleukin -33 (IL-33) ranked among top up-regulated cytokines in incised tissues of INC pain model mice. IL-33 was predominantly expressed in keratinocytes around the incisional area. Neutralization of IL-33 or its receptor suppression of tumorigenicity 2 protein (ST2) or genetic deletion of St2 gene (St2 -/-) remarkably ameliorated mechanical allodynia and improved gait impairments of model mice. IL-33 contributes to INC pain by recruiting macrophages, which subsequently release ROS in incised tissues via ST2-dependent mechanism. Transfer of excessive macrophages enhanced oxidative injury and reproduced mechanical allodynia in St2 -/- mice upon tissue incision. Overproduced ROS subsequently activated functionally up-regulated transient receptor potential ankyrin subtype-1 (TRPA1) channel innervating the incisional site to produce mechanical allodynia. Neither deleting St2 nor attenuating ROS affected wound healing of model mice. Conclusions: Our work uncovered a previously unrecognized contribution of IL-33/ST2 signaling in mediating mechanical allodynia and gait impairment of a mouse model of INC pain. Targeting IL-33/ST2 signaling could be a novel therapeutic approach for INC pain management.

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AIMS: Chronic pain is highly associated with anxiety. Electroacupuncture (EA) is effective in relieving pain and anxiety. Currently, little is known about the neural mechanisms underlying the comorbidity of chronic pain and anxiety and the EA mechanism. This study investigated a potential neural circuit underlying the comorbid and EA mechanisms. METHODS: Spared nerve injury (SNI) surgery established the chronic neuropathic pain mouse model. The neural circuit was activated or inhibited using the chemogenetic method to explore the relationship between the neural circuit and mechanical allodynia and anxiety-like behaviors. EA combined with the chemogenetic method was used to explore whether the effects of EA were related to this neural circuit. RESULTS: EA attenuated mechanical allodynia and anxiety-like behaviors in SNI mice, which may be associated with the activity of CaMKII neurons in the basolateral amygdala (BLA). Inhibition of BLACaMKII-rACC induced mechanical allodynia and anxiety-like behaviors in sham mice. Activation of the BLACaMKII-rACC alleviated neuropathic pain and anxiety-like behaviors in SNI mice. The analgesic and anxiolytic effects of 2 Hz EA were antagonized by the inhibition of the BLACaMKII-rACC. CONCLUSION: BLACaMKII-rACC mediates mechanical allodynia and anxiety-like behaviors. The analgesic and anxiolytic effects of 2 Hz EA may be associated with the BLACaMKII-rACC.

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Introduction: Diabetic peripheral neuropathy (DPN) affects patients' quality of life significantly. To date, selecting the appropriate treatment remains challenging. While electroacupuncture (EA) has shown promise as an effective adjunct therapy for DPN, and infrared thermography (IRT) has been considered as a potential predictor of treatment efficacy, the evidence for both remains inconclusive. As such, the objectives of this trial are twofold: to ascertain the efficacy of EA for DPN, and to explore the feasibility of IRT as an adjunctive objective tool for efficacy assessment. Methods: The study was designed as a randomized, parallel, controlled trial. It spanned over 6 weeks of treatment and an additional 4 weeks of follow-up. 104 eligible participants will be stratified for severity of disease: mild with Toronto clinical scoring system(TCSS) score 6-8, moderate (TCSS score 9-11), and severe (TCSS score 12-19), and each level will be randomised in a 1:1 ratio into a EA group and waiting-list group. The waiting-list group received only the current conventional medication, while the EA group received an additional 12 EA sessions on top of the conventional medication. The primary outcome indicators is nerve conduction velocity (NCV), which will be tested at the baseline and week 6. Total clinical efficiency, TCSS, Clinical symptoms score of Traditional Chinese Medicine (TCM), Patient global impression of change(PGIC), Temperature of regions of interest (ROIs), and Physico chemical examination will be used as secondary outcome indicators. In addition, safety assessment will be determined based on adverse events during the trial. Conclusion: The expected results of this study will determine whether EA improves efficacy in the treatment of DPN with an acceptable safety profile, and investigating variations in the efficacy of EA across different levels of DPN severity. Furthermore, it will explore the viability of IRT as an objective measure for evaluating treatment effectiveness for DPN. Clinical Trial Registration: ClinicalTrials.gov identifier, NCT06054087.

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Diabetic neuropathic pain (DNP) is a diabetic complication that causes severe pain and deeply impacts the quality of the sufferer's daily life. Currently, contemporary clinical treatments for DNP generally exhibit a deficiency in effectiveness. Electroacupuncture (EA) is recognized as a highly effective and safe treatment for DNP with few side effects. Regrettably, the processes via which EA alleviates DNP are still poorly characterized. Transient receptor potential vanilloid 1 (TRPV1) and phosphorylated calcium/calmodulin-dependent protein kinase II (p-CaMKII) are overexpressed on spinal cord dorsal horn (SCDH) in DNP rats, and co-localization is observed between them. Capsazepine, a TRPV1 antagonist, effectively reduced nociceptive hypersensitivity and downregulated the overexpression of phosphorylated CaMKIIα in rats with DNP. Conversely, the CaMKII inhibitor KN-93 did not have any impact on TRPV1. EA alleviated heightened sensitivity to pain caused by nociceptive stimuli and downregulated the level of TRPV1, p-CaMKIIα, and phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB) in DNP rats. Intrathecal injection of capsaicin, on the other hand, reversed the above effects of EA. These findings indicated that the CaMKII/CREB pathway on SCDH is located downstream of TRPV1 and is affected by TRPV1. EA alleviates DNP through the TRPV1-mediated CaMKII/CREB pathway.

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Comorbid chronic neuropathic pain and anxiety is a common disease that represents a major clinical challenge. The underlying mechanisms of chronic neuropathic pain and anxiety are not entirely understood, which limits the exploration of effective treatment methods. Glutamatergic neurons in the ventrolateral periaqueductal gray (vlPAG) have been implicated in regulating pain, but the potential roles of the vlPAG in neuropathic pain-induced anxiety have not been investigated. Herein, whole-cell recording and immunofluorescence showed that the excitability of CamkIIα neurons in the vlPAG (vlPAGCamkIIα+ neurons) was decreased in mice with spared nerve injury (SNI), while electroacupuncture (EA) activated these neurons. We also showed that chemogenetic inhibition of vlPAGCamkIIα+ neurons resulted in allodynia and anxiety-like behaviors in naive mice. Furthermore, chemogenetic activation of vlPAGCamkIIα+ neurons reduced anxiety-like behaviors and allodynia in mice with SNI, and EA had a similar effect in alleviating these symptoms. Nevertheless, EA combined with chemogenetic activation failed to further relieve allodynia and anxiety-like behaviors. Artificial inhibition of vlPAGCamkIIα+ neurons abolished the analgesic and anxiolytic effects of EA. Overall, our study reveals a novel mechanism of neuropathic pain-induced anxiety and shows that EA may relieve comorbid chronic neuropathic pain and anxiety by activating vlPAGCamkIIα+ neurons.

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Background: Gouty arthritis causes severe pain and inflammation. Alginate oligosaccharides (AOSs) are natural products derived from alginate and have anti-inflammatory properties. We explored the potential effects of AOSs with different degrees of polymerization (Dp) on gouty arthritis and associated mechanisms. Methods: We established a mouse model of gouty arthritis by injecting monosodium urate (MSU) into ankle joint. Nocifensive behavior, gait and ankle swelling were used to study AOS's effects. Biochemical assays, in vivo imaging, live cell Ca2+ imaging, electrophysiology, RNA-sequencing, etc. were used for mechanism exploration. Results: AOS2 (Dp=2), AOS3 (Dp=3) and AOS4 (Dp=4) all inhibited ankle swelling, whereas AOS2&3 produced the most obvious analgesia on model mice. AOS3, which was picked for further evaluation, produced dose-dependent ameliorative effects on model mice. AOS3 reversed gait impairments but did not alter locomotor activity. AOS3 inhibited NLRP3 inflammasome activation and inflammatory cytokine up-regulation in ankle joint. AOS3 ameliorated MSU-induced oxidative stress and reactive oxygen species (ROS) production both in vivo and in vitro and reversed the impaired mitochondrial bioenergetics. AOS3 activated the Nrf2 pathway and promoted Nrf2 disassociation from Keap1-bound complex and Nrf2 nuclear translocation, thus facilitating antioxidant gene expression via Nrf2-dependent mechanism. Nrf2 gene deficiency abolished AOS3's ameliorative effects on pain, inflammation and oxidative stress in ankle joints of model mice. AOS3 reduced TRPV1 functional enhancement in DRG neurons and constrained neuroactive peptide release. Conclusions: AOS3 ameliorates gouty arthritis via activating Nrf2-dependent antioxidant signaling, resulting in suppression of ROS-mediated NLRP3 inflammasome activation and TRPV1 enhancement. AOS3 may be novel therapeutics for gouty arthritis.

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Objectives: To summarize development processes and research hotspots of infrared imaging technology research on acupuncture and to provide new insights for researchers in future studies. Methods: Publications regarding infrared imaging technology in acupuncture from 2008 to 2023 were downloaded from the Web of Science Core Collection (WoSCC). VOSviewer 1.6.19, CiteSpace 6.2.R4, Scimago Graphica, and Microsoft Excel software were used for bibliometric analyses. The main analyses include collaboration analyses between countries, institutions, authors, and journals, as well as analyses on keywords and references. Results: A total of 346 publications were retrieved from 2008 to 2023. The quantity of yearly publications increased steadily, with some fluctuations over the past 15 years. "Evidence-Based Complementary and Alternative Medicine" and "American Journal of Chinese Medicine" were the top-cited journals in frequency and centrality. China has the largest number of publications, with the Shanghai University of Traditional Chinese Medicine being the most prolific institution. Among authors, Litscher Gerhard from Austria (currently Swiss University of Traditional Chinese Medicine, Switzerland) in Europe, was the most published and most cited author. The article published by Rojas RF was the most discussed among the cited references. Common keywords included "Acupuncture," "Near infrared spectroscopy," and "Temperature," among others. Explore the relationship between acupoints and temperature through infrared thermography technology (IRT), evaluate pain objectively by functional near-infrared spectroscopy (fNIRS), and explore acupuncture for functional connectivity between brain regions were the hotspots and frontier trends in this field. Conclusion: This study is the first to use bibliometric methods to explore the hotspots and cutting-edge issues in the application of infrared imaging technology in the field of acupuncture. It offers a fresh perspective on infrared imaging technology research on acupuncture and gives scholars useful data to determine the field's hotspots, present state of affairs, and frontier trends.

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BACKGROUND: Acupuncture stands out as a prominent complementary and alternative medicine therapy employed for functional dyspepsia (FD). We conducted a Bayesian meta-analysis to ascertain both the relative effectiveness and safety of various acupuncture methods in the treatment of functional dyspepsia. METHODS: We systematically searched eight electronic databases, spanning from their inception to April 2023. The eligibility criteria included randomized controlled trials investigating acupuncture treatments for FD. Study appraisal was conducted using the Cochrane risk of bias tool. Pairwise and network meta-analyses were conducted using RevMan 5.3 and ADDIS V.1.16.6 software. Bayesian network meta-analysis was performed to compare and rank the efficacy of different acupuncture therapies for FD symptoms. RESULTS: This study found that combining different acupuncture methods or using acupuncture in conjunction with Western medicine is more effective in improving symptoms of functional dyspepsia compared to using Western medicine alone. According to the comprehensive analysis results, notably, the combination of Western medicine and acupuncture exhibited superior efficacy in alleviating early satiation and postprandial fullness symptoms. For ameliorating epigastric pain, acupuncture combined with moxibustion proved to be the most effective treatment, while moxibustion emerged as the optimal choice for addressing burning sensations. Warming needle was identified as the preferred method for promoting motilin levels. CONCLUSION: The findings of this study demonstrate that acupuncture, both independently and in conjunction with other modalities, emerged as a secure and effective treatment option for patients with functional dyspepsia.

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BACKGROUND: Trigeminal neuralgia (TN) is difficult to treat due to its severe pain intensity and recurring episodes, which significantly impact quality of life. OBJECTIVES: We aimed to assess the effectiveness of electroacupuncture (EA) in alleviating the pain intensity in TN, and to determine whether EA combined with low-dosage carbamazepine (CBZ) has a synergistic effect. METHODS: A multi-centre, randomized, 2 × 2 factorial trial was conducted. Participants who met the inclusion criteria received active EA or sham EA for 60 min, three times a week for four weeks; CBZ (300 mg per day) or placebo for four weeks. The primary outcome was the change in visual analog scale (VAS) score from baseline to weeks 2, 4, 16, and 28. Secondary outcomes included quality of life and adverse events. RESULTS: A total of 120 participants (75 females and 45 males; mean (SD) age, 58.5 (15.3) years) were included. The main effects of EA and CBZ were significant (P < 0.001), and there was a significant interaction was identified between the interventions (P = 0.041). Participants who received EA (mean difference [MD], -0.3 [95% CI, -0.40 to -0.20] at week 2; -1.6 [-1.70 to -1.50] at week 4; -1.1 [-1.31 to -0.89] at week 16; -0.8 [-1.01 to -0.59] at week 28), CBZ (MD, -0.6 [95% CI, -0.70 to -0.50] at week 2; -0.9 [-1.03 to -0.77] at week 4, -0.2 [-0.41 to 0.01] at week 16, 0.2 [-0.01 to 0.41] at week 28), and the combination of both (MD, -1.8 [95% CI, -1.90 to -1.70] at week 2; -3.7 [-3.83 to -3.57] at week 4, -3.4 [-3.61 to -3.19] at week 16, -2.9 [-3.11 to -2.69] at week 28) had a greater reduction in VAS score over the treatment phase than their respective control groups (sham EA, placebo, and sham EA plus placebo). EA-related adverse events (6/59, 10.17%) were lower than that of CBZ (15/59, 25.42%) during the whole phases. CONCLUSIONS: EA or CBZ alone are effective treatments for TN, while the combination of EA and low-dosage CBZ exerts a greater benefit. These findings in this trial demonstrate that the combination of EA and low-dosage CBZ may be clinically effective under certain circumstances. TRIAL REGISTRATION: NCT03580317.

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BACKGROUND: Diabetic peripheral neuropathy (DPN) is a chronic complication of diabetes mellitus, which is the most common neuropathy worldwide. Owing to the inadequacies of existing treatment methods, managing DPN remains a significant challenge. Studies suggest that electroacupuncture (EA) could potentially serve as a beneficial alternative treatment for this condition. Nevertheless, there is still inadequate proof of its therapeutic effectiveness and safety. As a result, the goal of this protocol is to methodically compile the data pertaining to the effectiveness and security of EA in the management of DPN. METHODS: To find appropriate randomized controlled trials (RCTs), nine reliable databases in the English and Chinese languages will be examined. RevMan5.3 will be used to combine the retrieved data and perform meta-analyses. The methodological quality of the included RCTs will be evaluated using the Cochrane Risk of Bias Assessment 2.0 tool. The Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) system will be utilized to evaluate the degree of strength and certainty of the evidence. We will also perform publication bias, sensitivity and subgroup analyses. DISCUSSION: This protocol describes the intended scope and approach for a forthcoming systematic review and meta-analysis that will inform therapeutic decision-making by offering current information on the efficacy and safety of EA in the treatment of DPN. The results of the study will help standardize strategies for EA in the treatment of DPN.

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Gouty arthritis evokes joint pain and inflammation. Mechanisms driving gout pain and inflammation remain incompletely understood. Here we show that CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to drive gout pain and inflammation. CXCL5 expression was increased in ankle joints of gout arthritis model mice, whereas CXCR2 showed expression in joint-innervating sensory neurons. CXCL5 activates CXCR2 expressed on nociceptive sensory neurons to trigger TRPA1 activation, resulting in hyperexcitability and pain. Neuronal CXCR2 coordinates with neutrophilic CXCR2 to contribute to CXCL5-induced neutrophil chemotaxis via triggering CGRP- and substance P-mediated vasodilation and plasma extravasation. Neuronal Cxcr2 deletion ameliorates joint pain, neutrophil infiltration and gait impairment in model mice. We confirmed CXCR2 expression in human dorsal root ganglion neurons and CXCL5 level upregulation in serum from male patients with gouty arthritis. Our study demonstrates CXCL5-neuronal CXCR2-TRPA1 axis contributes to gouty arthritis pain, neutrophil influx and inflammation that expands our knowledge of immunomodulation capability of nociceptive sensory neurons.

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Allergic contact dermatitis (ACD) is a common skin disease featured with skin inflammation and a mixed itch/pain sensation. The itch/pain causes the desire to scratch, affecting both physical and psychological aspects of patients. Nevertheless, the mechanisms underlying itch/pain sensation of ACD still remain elusive. Here, we found that oxidative stress and oxidation-related injury were remarkably increased in the inflamed skin of a mouse model of ACD. Reducing oxidative stress significantly attenuated itch/pain-related scratching, allokonesis and skin inflammation. RNA-Sequencing reveals oxidative stress contributes to a series of skin biological processes, including inflammation and immune response. Attenuating oxidative stress reduces overproduction of IL-1ß and IL-33, two critical cytokines involved in inflammation and pain/itch, in the inflamed skin of model mice. Exogenously injecting H2O2 into the neck skin of naïve mice triggered IL-33 overproduction in skin keratinocytes and induced scratching, which was reduced in mice deficient in IL-33 receptor ST2. ACD model mice showed remarkable neutrophil infiltration in the inflamed skin. Blocking neutrophil infiltration reduced oxidative stress and attenuated scratching and skin inflammation. Therefore, our study reveals a critical contribution of neutrophil-derived oxidative stress to skin inflammation and itch/pain-related scratching of ACD model mice via mechanisms involving the triggering of IL-33 overproduction in skin keratinocytes. Targeting skin oxidative stress may represent an effective therapy for ameliorating ACD.

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Diabetic neuropathic pain (DNP) is a frequent complication of diabetes. Calcium/calmodulin-dependent protein kinase II α (CaMKIIα), a multi-functional serine/threonine kinase subunit, is mainly located in the surface layer of the spinal cord dorsal horn (SCDH) and the primary sensory neurons in dorsal root ganglion (DRG). Numerous studies have indicated electroacupuncture (EA) takes effect in various kinds of pain. In this research, we explored whether CaMKIIα on rats' SCDH and DRG participated in DNP and further explored the mechanisms underlying the analgesic effects of EA. The DNP model in rats was successfully established by intraperitoneal injection of streptozotocin. Certain DNP rats were treated with intrathecal injections of KN93, a CaMKII antagonist, and some of the DNP rats received EA intervention. The general conditions, behaviors, the expressions of CaMKIIα and phosphorylated CaMKIIα (p-CaMKIIα) were evaluated. DNP rats' paw withdrawal threshold was reduced and the expressions of p-CaMKIIα in SCDH and DRG were upregulated compared with the Normal group, while the level of CaMKIIα showed no significance. KN93 attenuated DNP rats' hyperalgesia and reduced the expressions of p-CaMKIIα. We also found EA attenuated the hyperalgesia of DNP rats and reduced the expressions of p-CaMKIIα. The above findings suggest that p-CaMKIIα in SCDH and DRG is involved in DNP. The analgesic effect of EA in DNP might be related to the downregulation of p-CaMKIIα expression level. Our study further supports that EA can be an effective clinical treatment for DNP.

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Neurons within the anterior cingulate cortex (ACC) orchestrate the co-occurrence of chronic pain and anxiety. The ACC hyperactivity plays a crucial role in the emotional impact of neuropathic pain. Astrocyte-mediated neuroinflammatory is responsible for regulating the balance between excitation-inhibition (E/I) in the brain. However, there is limited understanding of the possible contributions of astrocytes in the ACC to comorbidity of anxiety and chronic inflammatory pain. This paper aims to investigate the possible contribution of astrocytes in the ACC to the comorbidity between anxiety and chronic inflammatory pain, as well as their involvement in the E/I imbalance of pyramidal cells. Our results show that CFA rats displayed allodynia and anxiety-like behaviors. The E/I balance in the ACC shifts to excitement in comorbidity of chronic pain and anxiety by western blotting, and electrophysiological recording. Result of RNA-Seq also indicated that E/I imbalance and neuroinflammation of ACC were involved in pain-anxiety comorbidity. Then, positive cells of GFAP but not Iba1 in the contralateral ACC were increased; the mRNA expression of GFAP and its activation-related proinflammatory cytokines (TNF-α, IL-6, and IL-1ß) in the contralateral ACC were also elevated. Furthermore, specific chemogenic inhibition of ACC astrocytes reversed comorbid pain and anxiety and suppressed high ACC excitability. Our data suggest that astrocytes participate in comorbid pain and anxiety and excitation-inhibition imbalance in ACC. Inhibition astrocyte activation can reduce anxiety related to pain and restore the imbalance in the ACC. These findings shed light on the involvement of astrocytes in comorbid conditions, offering valuable insights into a potential therapeutic approach for the co-occurrence of chronic pain and anxiety.

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Recent studies have confirmed that pain memory is often accompanied by negative emotions. Electroacupuncture (EA) can block the retrieval of painful memories, thereby alleviating the associated negative behaviors. However, the underlying mechanism is poorly understood. This study revealed that the effect of EA on pain memory-induced negative behaviors is related to the mediation of GABAergic neuron activity and GABA receptor expression in the rostral anterior cingulate cortex (rACC). Previous studies have shown that the rACC is a crucial area for regulating nociceptive behaviors and negative emotions in pain memory models. The GABAergic neurons and receptors in the rACC are largely involved in pain sensation and related effects. However, the relationships among pain memory, GABAergic neurons and receptors in the rACC have not been investigated. In this study, we established a pain memory model via secondary plantar cross-injection of carrageenan and EA treatment. Using chemogenetic methods and behavioral assessments of pain and negative emotion, we found that early excitation of GABAergic neurons in the rACC blocked the recall of pain memories and reduced anxiety-like behaviors in pain memory model rats. Furthermore, pharmacological methods revealed that excitation of GABAA and GABAB receptors in the rACC blocks hyperpathia associated with pain memory and pain-induced anxiety-like behaviors, while inhibition of GABAA and GABAB receptors reverses these effects. These results suggest that EA may alleviate pain and associated anxiety-like behaviors related to pain memories through the activation of GABAergic neurons and excitation of GABAA and GABAB receptors in the rACC.

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BACKGROUND: Postherpetic neuralgia (PHN) is the most common complication of herpes zoster infection and affects patients' quality of life. Acupuncture therapy is regarded as a competitive method of treatment for analgesia. OBJECTIVE: To summarize evidence from systematic reviews (SRs) and evaluate the effectiveness and safety of different acupuncture therapies for treating PHN. METHODS: Eight electronic databases were searched from their inception to August 5, 2022, including 4 international electronic databases (PubMed, EMBASE, the Cochrane Library, and Web of Science) and 4 Chinese databases (Chinese Biomedical Database, China National Knowledge Infrastructure, VIP Database and Wanfang Database). Methodological quality was assessed by A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2). The Risk of Bias in Systematic Review (ROBIS) tool was used to assess the risk of bias in SRs. Evidence level was assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Totally, 7 SRs were included, including 128 studies and 9,792 patients. In AMSTAR 2, most of the SRs were of low or critically low levels since they had more than 1 critical deficiency. In ROBIS, 1 SR (14.29%) was rated as high risk, and the other 6 (85.71%) were rated as low risk. In the GRADE system, 9 outcomes (28.13%) were valued as high level, 5 (15.63%) as moderate level, 1 (3.13%) as low, and 17 (53.13%) as very low. In the effectiveness of acupuncture therapy, the group "moxibustion vs. original medical treatment" [mean difference (MD)=-1.44, 95% confidence interval (CI): -1.80 to -1.08, I2=99%, P<0.00001] was of the highest heterogeneity and the group "bloodletting vs. original medical treatment" (MD=-2.80, 95% CI: -3.14 to -2.46, I2=0, P<0.00001) was of the lowest heterogeneity. Six SRs have reported the safety of their studies and no serious events were shown in the treatment and control groups. CONCLUSIONS: Acupuncture therapy seems to be effective in treating PHN. Despite the evidence that suggested the advantages of acupuncture therapy in relieving pain and promoting efficacy and safety, the methodological quality was quite low. Further studies should pay more attention to the quality of original studies and evidence for SRs to confirm these findings. (PROSPERO registration No. CRD42022344790).

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AIMS: Negative emotions induced by chronic pain are a serious clinical problem. Electroacupuncture (EA) is a clinically proven safe and effective method to manage pain-related negative emotions. However, the circuit mechanisms underlying the effect of EA treatment on negative emotions remain unclear. METHODS: Plantar injection of complete Freund's adjuvant (CFA) was performed to establish a rat model of chronic inflammatory pain-induced anxiety-like behaviors. Adeno-associated virus (AAV) tracing was used to identify excitatory synaptic transmission from the rostral anterior cingulate cortex (rACC) to the dorsal raphe nucleus (DRN). Employing chemogenetic approaches, we examined the role of the rACC-DRN circuit in chronic pain-induced anxiety-like behaviors and investigated whether EA could reverse chronic pain-induced dysfunctions of the rACC-DRN circuit and anxiety-like behaviors. RESULTS: We found that chemogenetic activation of the rACC-DRN circuit alleviated CFA-induced anxiety-like behaviors, while chemogenetic inhibition of the rACC-DRN circuit resulted in short-term CFA-induced anxiety-like behaviors. Further research revealed that the development of CFA-induced anxiety-like behaviors was attributed to the dysfunction of rACC CaMKII neurons projecting to DRN serotonergic neurons (rACCCaMKII-DRN5-HT neurons) but not rACC CaMKII neurons projecting to DRN GABAergic neurons (rACCCaMKII-DRNGABA neurons). This is supported by the findings that chemogenetic activation of the rACCCaMKII-DRN5-HT circuit alleviates anxiety-like behaviors in rats with chronic pain, whereas neither chemogenetic inhibition nor chemogenetic activation of the rACCCaMKII-DRNGABA circuit altered CFA chronic pain-evoked anxiety-like behaviors in rats. More importantly, we found that EA could reverse chronic pain-induced changes in the activity of rACC CaMKII neurons and DRN 5-HTergic neurons and that chemogenetic inhibition of the rACCCaMKII-DRN5-HT circuit blocked the therapeutic effects of EA on chronic pain-induced anxiety-like behaviors. CONCLUSIONS: Our data suggest that the reversal of rACCCaMKII-DRN5-HT circuit dysfunction may be a mechanism underlying the therapeutic effect of EA on chronic pain-induced anxiety-like behaviors.

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PURPOSE: The opioid crisis resulting from its use disorder and overdose poses additional challenges for cancer pain management. The American Society of Clinical Oncology Practice Guideline recommends acupuncture therapy for the management of adult cancer-related pain (CRP), but the effectiveness of transcutaneous electrical acupoint stimulation (TEAS) on CRP remains uncertain. METHODS: This 5-week prospective randomized clinical trial was conducted at 2 hospitals in China, and participants with CRP receiving chronic opioid therapy were randomized 1:1 into two groups between December 2014 and June 2018. The true TEAS group underwent 15 sessions of TEAS treatments over 3 consecutive weeks, while the control group received sham stimulation. The primary outcome was the numerical rating scale (NRS) score in the past 24h at week 3. The secondary outcomes included morphine equivalent daily dose, quality of life and adverse events. RESULTS: A total of 159 participants were included in the modified intention-to-treat population. The baseline characteristics were similar in both groups. The mean NRS scores were 0.98 points at week 3 in the true TEAS group and 1.41 points in the sham group, with the mean difference between groups of -0.43 points (P < 0.001; OR = 0.68, P < 0.05). The proportion of patients with NRS reduction more than thirty percentage at week 3 was 50.00% in the true TEAS group and 35.44% in the sham group (RD = 0.15, P > 0.05; RR = 1.41, P > 0.05). No significant difference in pain intensity between the two groups was observed during the follow-up period without TEAS intervention (week 4, OR = 0.83, P > 0.05; week 5, OR = 0.83, P > 0.05). The Karnofsky Performance Status value suggested that patients in the true TEAS group experienced an improved quality of life (Between-group differences: week 3, 3.5%, P < 0.05; week 4, 4.6%, P < 0.001; week 5, 5.6%, P < 0.001). CONCLUSIONS: The 3-week application of TEAS in patients with CRP receiving chronic opioid therapy resulted in a statistically significant reduction in pain scores, but the observed reduction was of uncertain clinical significance. The prolonged analgesic effect of TEAS was not confirmed in this trial. CLINICALTRIAL: GOV: ChiCTR-TRC-13003803.

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Background: Major depressive disorder (MDD) is highly prevalent, affecting more than 300 million individuals worldwide, and its occurrence may be related to the abnormality of the prefrontal cortex and bilateral temporal cortex. Acupuncture, rooted in the theories of acupoints and meridians, has demonstrated its efficacy in regulating cortical blood flow (CBF) in the brains of MDD patients. As one form of acupuncture, intradermal acupuncture (IA) can alleviate clinical symptoms such as depressive mood and insomnia in MDD patients. However, it remains unknown whether IA will have a specific effect on the prefrontal cortex and bilateral temporal cortex in MDD patients. Methods: In total, 60 participants will be recruited: 20 healthy control participants and 40 MDD patients. All healthy control participants will be allocated to the control group, whereas the 40 MDD patients will be randomly divided into two groups: the gallbladder meridian acupoint (GBA) group and the non-acupoint (NA) group, at a 1:1 allocation ratio. All groups will undergo a one-time IA intervention while their cortical activity is monitored using functional near-infrared spectroscopy (fNIRS). Total hemoglobin, oxygenated hemoglobin, and deoxygenated hemoglobin of the prefrontal and bilateral temporal cortices will be measured by fNIRS during the test procedure. Discussion: This trial aims to use fNIRS to compare real-time hemodynamic changes in the prefrontal and bilateral temporal cortices of healthy individuals and MDD patients during IA. The primary objective is to investigate whether MDD patients exhibit specific real-time responses to IA stimulation in these brain regions. The findings from this study will provide clinical data and a possible theoretical basis for the assumption that stimulation of IA may treat MDD by modulating the relevant brain regions. Trial Registration: The study protocol has been registered in the clinicaltrials.gov with the code NCT05707299.

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Diabetic neuropathic pain (DNP) is a common and destructive complication of diabetes mellitus. The discovery of effective therapeutic methods for DNP is vitally imperative because of the lack of effective treatments. Although 2 Hz electroacupuncture (EA) was a successful approach for relieving DNP, the mechanism underlying the effect of EA on DNP is still poorly understood. Here, we established a rat model of DNP that was induced by streptozotocin (STZ) injection. P2X4R was upregulated in the spinal cord after STZ-injection. The upregulation of P2X4R was mainly expressed on activated microglia. Intrathecal injection of a P2X4R antagonist or microglia inhibitor attenuated STZ-induced nociceptive thermal hyperalgesia and reduced the overexpression of brain-derived neurotrophic factor (BDNF), interleukin-1ß (IL-1ß) and tumor necrosis factor-α (TNF-α) in the spinal cord. We also assessed the effects of EA treatment on the pain hypersensitivities of DNP rats, and further investigated the possible mechanism underlying the analgesic effect of EA. EA relieved the hyperalgesia of DNP. In terms of mechanism, EA reduced the upregulation of P2X4R on activated microglia and decreased BDNF, IL-1ß and TNF-α in the spinal cord. Mechanistic research of EA's analgesic impact would be beneficial in ensuring its prospective therapeutic effect on DNP as well as in extending EA's applicability.