Comorbidity of chronic pain and major depression disorder (MDD) are common diseases. However, the mechanisms of electroacupuncture (EA) and the responses of N‐methyl‐D‐aspartate receptors in the brain remain unclear. Three injections of complete Freund′s adjuvant (CFA) were administered to induce chronic inflammatory pain (CIP). EA was then performed once every other day from days 14 to 28. Behavior tests of chronic pain and depression were evaluated to make sure of the successful induction of comorbidity. We used Western blotting to analyze brain tissue from the prefrontal cortex (PFC), hippocampus, and hypothalamus for levels of phosphorylated N‐methyl‐D‐aspartate receptor subunit 1 (pNR1), NR1, pNR2B, NR2B, and calcium/calmodulin‐dependent protein kinase type II alpha isoform (pCaMKIIα). The mechanical hyperalgesia, thermal hyperalgesia, and depression were observed in the CIP group. Furthermore, decreased levels of N‐methyl‐D‐aspartate receptors (NMDARs) were also noted. Not Sham EA but EA reversed chronic pain and depression as well as the decreased levels of NMDA in the signaling pathway. The CFA injections successfully induced a significant comorbidity model. EA treated the comorbidity by upregulating the NMDA signaling pathway in the PFC, hippocampus, and hypothalamus. Our results indicated significant mechanisms of comorbidity of chronic pain and MDD and EA‐analgesia that involves the regulation of the NMDAR signaling pathway. These findings may be relevant to the evaluation and treatment of comorbidity of chronic pain and MDD.

Peripheral tissue damage and associated inflammation can trigger neuroplastic changes in somatic pain pathways, such as reduced neuronal firing thresholds and synaptic potentiation, that ultimately lead to peripheral sensitization and chronic pain. Electroacupuncture (EA) can relieve chronic inflammatory pain, but the underlying mechanisms are unknown, including the contributions of higher pain centers such as somatosensory cortex (SSC). We investigated these mechanisms using optogenetic modulation of SSC activity in a mouse inflammatory pain model. Injection of Complete Freund's Adjuvant into the hind paw reliably induced inflammation accompanied by reduced mechanical and thermal pain thresholds (hyperalgesia) within three days (mechanical: 1.54 ± 0.13 g; thermal: 3.94 ± 0.43 s). Application of EA produced significant thermal and mechanical analgesia, but these responses were reversed by optogenetic activation of SSC neurons, suggesting that EA-induced analgesia involves modulation of central pain pathways. Western blot and immunostaining revealed that EA also attenuated CaMKIIα signaling in the dorsal root ganglion, central spinal cord, SSC, and anterior cingulate cortex (ACC). In contrast, optogenetic activation of the SSC induced CaMKIIα signaling in SSC and ACC. These findings suggest that AE can relieve inflammatory pain by suppressing CaMKIIα-dependent plasticity in cortical pain pathways. The SSC and ACC CaMKIIα signaling pathways may be valuable therapeutic targets for chronic inflammatory pain treatment.

(1) Background: The medical practice of acupuncture involves the insertion of a specialized stainless needle into a specific body point, often called an acupoint, to initiate a perceived phenomenon of de-qi sensation. Therefore, the term “de-qi” describes bodily sensations experienced by the recipient during acupuncture, which may include feelings of soreness, heaviness, fullness, numbness, and migration. However, while acupuncture treatments reportedly result in acupoint activation and an increased release of neurotransmitters or cytokines, detecting these substances released into the acupoint microenvironment is often missed or delayed in clinical and basic practice. (2) Methods: To address this situation, we employed a paper-based enzyme-linked immunosorbent assay method to examine acupoint environmental changes using minute volumes of easily accessible acupoint fluids. (3) Results: Our results indicated that while levels of adenosine triphosphate (ATP), interleukin-1β, interleukin-6, glutamate, substance P, and histamine were all increased in the experimental group following electroacupuncture (EA) treatment, contrary results were observed in the sham EA and transient receptor potential vanilloid 1 (Trpv1^−/−) groups. Subsequently, TRPV1 and its associated molecules were augmented in mouse dorsal root ganglion, spinal cord, thalamus, and the somatosensory cortex, then examined by Western blotting and immunofluorescence techniques. Investigations revealed that these elevations were still unobserved in the sham EA or EA in the Trpv1^−/− groups. Furthermore, results showed that while administering ATP could mimic EA function, it could be reversed by the ATP P2 receptor antagonist, suramin. (4) Conclusions: Our data provide novel information, indicating that changes in neurotransmitter and cytokine levels can offer insight into acupuncture mechanisms and clinical targeting.

Background and Purpose. The effect of acupuncture as treatment for poststroke complications is questionable. We performed a randomized, sham‐controlled double‐blind study to investigate it. Methods. Patients with first‐time acute stroke were randomized to receive 24 sessions of either real or sham acupuncture during an eight‐week period. The primary outcome measure was change in National Institute of Health Stroke Scale (NIHSS) score. Secondary outcome measures included changes in Barthel Index (BI), Instrumental Activities of Daily Living (IADL), Hamilton Depression Rating Scale (HAM‐D), and Visual Analogue Scale (VAS) for pain scores. Results. Of the 52 patients who were randomized to receive acupuncture (n = 28) or placebo (n = 24), 10 patients in the acupuncture group and 9 patients in the placebo group failed to complete the treatment. In total, 18 patients in the acupuncture group and 15 patients in the control group completed the treatment course. Reduction in pain was significantly greater in the acupuncture group than in the control group (p value = 0.04). There were no significant differences in the other measures between the two groups. Conclusions. Acupuncture provided more effective poststroke pain relief than sham acupuncture treatment. However, acupuncture had no better effect on neurological, functional, and psychological improvement.

Background: Fibromyalgia (FM) is characterized by complex pain symptoms lacking impersonal considerations in diagnosis and treatment evaluation, which often happens in women. Chronic and persistent widespread pain is the key symptom disturbing patients with FM, leading to depression, obesity, and sleep disturbances. Toll-like receptor 4 (TLR4) activation produces a harmful sensory input involved in central pain; this is the focus of this study. Electroacupuncture (EA) has beneficial effects in reducing FM pain, but its connection with TLR4 signaling is still unknown. Methods: Intermittent cold stress significantly induced mechanical and thermal pain. EA, but not sham EA, reliably attenuated mechanical and thermal hyperalgesia. The increased inflammatory mediators in FM mice were reduced in the EA group, but not in the sham group. Results: All TLR4 and related molecule levels increased in the FM mice’s hypothalamus, periaqueductal gray (PAG), and cerebellum. These increases could be attenuated by EA but not sham stimulation. Activation of TLR4 by lipopolysaccharide (LPS) significantly induced FM and can be further reversed by a TLR4 antagonist. Conclusions: These mechanisms provide evidence that the analgesic effect of EA is related to the TLR4 pathway. In addition, we showed that inflammation can activate the TLR4 pathway and provided new possible therapeutic targets for FM pain.

Background: Intracerebral hemorrhage (ICH) is the second most common stroke worldwide and is associated with high mortality rates. Despite established guidelines for ICH treatment, the prognosis of ICH remains poor. Traditional Chinese Medicine (TCM), including Chinese herbal medicine (CHM) and acupuncture, has been used as a complementary therapy; however, its long-term survival benefits remain uncertain. Methods: This study aimed to evaluate the effectiveness of TCM, including CHM and acupuncture, in reducing mortality among patients with ICH, using data from Taiwan’s National Health Insurance Research Database. This retrospective cohort study analyzed patients with ICH (ICD-9-CM: 430-432; ICD-10-CM: I60-I62) between 2000 and 2018. Patients who received TCM or acupuncture (≥2 outpatient or ≥1 inpatient visits) were matched 1:1 with non-TCM patients based on age, sex, urbanization, and income. Mortality was the primary outcome, analyzed using Cox proportional hazards models. Results: Among 6450 patients (3225 TCM; 3225 control), TCM, including CHM and acupuncture, was significantly associated with reduced all-cause mortality in patients with ICH (adjusted hazard ratio [aHR] = 0.42; 95% CI, 0.39-0.46; p < 0.001), with CHM alone showing aHR = 0.40 (95% CI, 0.35-0.45; p < 0.001) and CHM combined with acupuncture showing aHR = 0.43 (95% CI, 0.39-0.47; p < 0.001) compared with non-TCM users. Among the top 10 single herbs used, Di-Long exhibited the greatest reduction in mortality risk (aHR = 0.36; 95% CI, 0.28-0.47; p < 0.001). Among formulas, Xue-Fu-Zhu-Yu-Tang and Chai-Hu-Jia-Long-Gu-Mu-Li-Tang demonstrated the strongest protective associations with mortality (aHR = 0.35; p < 0.001). Network core pattern analysis identified the key components of treatment, including Bu-Yang-Huan-Wu-Tang, Yuan-Zhi, Shi-Chang-Pu, Tian-Ma, and Gou-Teng. Acupuncture exhibited a similar dose–response effect, with mortality risk decreasing progressively with more sessions (aHR: for ≥18 sessions: 0.45; 95% CI, 0.40-0.49; p < 0.001). Conclusion: CHM and acupuncture are associated with lower mortality in patients with ICH. Further research is needed to confirm these findings and explore the underlying mechanisms.