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Background Chronic pain is a major clinical problem with limited treatment options. Previous studies have demonstrated that activation of adenosine monophosphate-activated protein kinase (AMPK) can attenuate neuropathic pain. Inflammation/immune response at the site of complete Freund’s adjuvant (CFA) injection is known to be a critical trigger of the pathological changes that produce inflammatory pain. However, whether activation of AMPK produces an analgesic effect through inhibiting the proinflammatory cytokines, including interleukin-1β (IL-1β), in inflammatory pain remains unknown. Methods Inflammatory pain was induced in mice injected with CFA. The effects of AICAR (5-aminoimidazole-4-carboxyamide ribonucleoside, an AMPK activator), Compound C (an AMPK inhibitor), and IL-1ra (an IL-1 receptor antagonist) were tested at day 4 after CFA injection. Inflammatory pain was assessed with von Frey filaments and hot plate. Immunoblotting, hematoxylin and eosin (H&E) staining, and immunofluorescence were used to assess inflammation-induced biochemical changes. Results The AMPK activator AICAR produced an analgesic effect and inhibited the level of proinflammatory cytokine IL-1β in the inflamed skin in mice. Moreover, activation of AMPK suppressed CFA-induced NF-κB p65 translocation from the cytosol to the nucleus in activated macrophages (CD68 + and CX3CR1 + ) of inflamed skin tissues. Subcutaneous injection of IL-1ra attenuated CFA-induced inflammatory pain. The AMPK inhibitor Compound C and AMPKα shRNA reversed the analgesic effect of AICAR and the effects of AICAR on IL-1β and NF-κB activation in inflamed skin tissues. Conclusions Our study provides new information that AMPK activation produces the analgesic effect by inhibiting NF-κB activation and reducing the expression of IL-1β in inflammatory pain.

Inflammatory cytokines produced by muscularis macrophages largely contribute to the pathological signs of postoperative ileus (POI). Electroacupuncture (EA) can suppress inflammation, mainly or partly via activation of vagal efferent. The goal of this study was to investigate the mechanisms by which EA stimulation at an hindlimb region ameliorates inflammation in POI. Intestinal motility and inflammation were examined after 24 h after intestinal manipulation (IM)-induced POI in mice. Local immune response in the intestinal muscularis, expression of macrophages, α7 nicotinic acetylcholine receptor (α7nAChR), Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) were determined by flow cytometry, Western Blot, qPCR and immunofluorescence. The effects of α7nAChR antagonists (methyllycaconitine and α-bungarotoxin) and JAK2/STAT3 inhibitors (AG490 and WP1066) were also administered in a subset of mice prior to EA. In the parasympathetic pathways, intestinal motility and inflammation were determined after cervical vagotomy and sub-diaphragmatic vagotomy. The expression of gamma absorptiometry aminobutyric acid (GABA ) receptor in dorsal motor nucleus of vagal (DMV) cholinergic neurons was assessed by immunofluorescence and the response to DMV microinjection of bicuculine (antagonist of GABA receptor) or muscimol (agonist of GABA receptor) were assessed. EA suppressed intestinal inflammation and promoted gastrointestinal motility. Mechanistically, EA activated the α7nAChR-mediated JAK2/STAT3 signaling pathway in macrophages which reduced the production of inflammatory cytokines. Furthermore, we also demonstrated that hindlimb region stimulation drove vagal efferent output by inhibiting the expression of GABA receptor in DMV to ameliorate inflammation. The present study revealed that EA of hindlimb regions inhibited the expression of GABA receptor in DMV neurons, whose excited vagal nerve, in turn suppressed IM-induced inflammation via activation of α7nAChR-mediated JAK2/STAT3 signaling pathway.

The oxygen and nitrogen self-codoped activated carbon nanosheets are facilely prepared from chitosan by using ZnCl2. The optimal carbon possesses a significantly increased specific surface area (SBET = 1679 m2 g− 1) and richer porosity (Vp = 0.792 cm3 g− 1) in comparison with the pristine carbon prepared without using ZnCl2 (Vp = 0.035 cm3 g− 1, SBET = 80 m2 g− 1). The well-developed hierarchical porous structure and high heteroatom contents (N 7.35 at%, O 8.96 at%) endow the optimal carbon superior capacitive performance. It delivers a specific capacitance of 287.94 F g− 1 at 1.0 A g− 1 in the three-electrode supercapacitors. Moreover, the optimal carbon-based symmetric supercapacitor achieves an energy density of 28.74 Wh kg− 1 when the power density is 399.92 W kg− 1, and demonstrates satisfactory cycling stability. Our work provides an effective way for fabricating heteroatom self-doped porous carbon materials for advanced electrochemical energy storage devices.

This study aimed to establish the 90% effective interval time for programmed intermittent epidural bolus (PIEB) following dural puncture epidural (DPE) analgesia with a dexmedetomidine ropivacaine combination for primiparas in the first stage of labor. This biased coin up and down sequential allocation trial enrolled 40 nulliparous women requesting labor analgesia. After an initial loading dose, analgesia was maintained with PIEB of a fixed volume of 8 mL of the same solution, starting 1 hour later. The initial PIEB interval was set at 60 minutes for the first patient and subsequently adjusted by ± 5 minutes based on the outcome of the previous patient, following the biased-coin design. A successful interval was defined as no requirement for supplemental analgesia. The primary outcome was the 90% effective PIEB interval (ED90) for the first stage of labor. Secondary outcomes included patient satisfaction, the incidence of motor and sensory block, and adverse events. Isotonic regression analysis estimated the 90% effective PIEB interval as 34.5 min (95% confidence interval: 31.0-37.0 min). All patients reported a very high level of satisfaction. The incidence of motor block was 10%, while 37.5% of patients achieved the highest sensory block at the T6 level or above. Notably, no cases of excessive sedation, hypotension, or bradycardia. For DPE labor analgesia using 8 mL of 0.075% ropivacaine combined with 0.4 μg/mL dexmedetomidine, the optimal PIEB interval is approximately 35 min. This interval can reduce breakthrough pain and the need for rescue analgesia. This finding provides a practical, evidence-based reference for optimizing PIEB regimens in clinical labor analgesia, contributing to improved maternal comfort and labor experience while ensuring safety.

Chronic itch severely reduces the quality of life of patients. Electroacupuncture (EA) is widely used to treat chronic itch. However, the underlying mechanism of this therapeutic action of EA is largely unknown. Cannabinoid CB1 receptors in the ventrolateral periaqueductal gray (vlPAG) mediate the analgesic effect of EA. Using a dry skin-induced itch model in mice, we determined whether EA treatment reduces chronic itch via CB1 receptors in the vlPAG. We showed that the optimal inhibitory effect of EA on chronic itch was achieved at the high frequency and high intensity (100 Hz and 3 mA) at “Quchi” (LI11) and “Hegu” (LI14) acupoints, which are located in the same spinal dermatome as the cervical skin lesions. EA reversed the increased expression of CB1 receptors in the vlPAG and decreased the concentration of 5-hydroxytryptamine (5-HT) in the medulla oblongata and the expression of gastrin-releasing peptide receptors (GRPR) in the cervical spinal cord. Furthermore, knockout of CB1 receptors on GABAergic neurons in the vlPAG attenuated scratching behavior and the 5-HT concentration in the medulla oblongata. In contrast, knockout of CB1 receptors on glutamatergic neurons in the vlPAG blocked the antipruritic effects of EA and the inhibitory effect of EA on the 5-HT concentration in the medulla oblongata. Our findings suggest that EA treatment reduces chronic itch by activation of CB1 receptors on glutamatergic neurons and inhibition of CB1 receptors on GABAergic neurons in the vlPAG, thereby inhibiting the 5-HT release from the medulla oblongata to GRPR-expressing neurons in the spinal cord. Our findings suggest that EA attenuates chronic itch via activating CB1 receptors expressed on glutamatergic neurons and downregulating CB1 receptors on GABAergic neurons in the vlPAG, leading to the reduction in 5-HT release in the rostroventral medulla and GRPR signaling in the spinal cord. Our study not only advances our understanding of the mechanisms of the therapeutic effect of EA on chronic itch but also guides the selection of optimal parameters and acupoints of EA for treating chronic itch.

Although electroacupuncture (EA) has become a worldwide practice, little is understood about its precise target in the central nervous system (CNS) and the cell type-specific analgesia mechanism. In the present study, we found that EA has significant antinociceptive effects both in inflammatory and neuropathic pain models. Chemogenetic inhibition of GABAergic neurons in the ventrolateral periaqueductal gray (vlPAG) replicated the effects of EA, whereas the combination of chemogenetic activation of GABAergic neurons and chemogenetic inhibition of glutamatergic neurons in the vlPAG was needed to reverse the effects of EA. Specifically knocking out CB1 receptors on GABAergic neurons in the vlPAG abolished the EA effect on pain hypersensitivity, while specifically knocking out CB1 receptors on glutamatergic neurons attenuated only a small portion of the EA effect. EA synchronously inhibits GABAergic neurons and activates glutamatergic neurons in the vlPAG through CB1 receptors to produce EA-induced analgesia. The CB1 receptors on GABAergic neurons localized in the vlPAG was the basis of the EA effect on pain hypersensitivity. This study provides new experimental evidence that EA can bidirectionally regulate GABAergic neurons and glutamatergic neurons via the CB1 receptors of the vlPAG to produce analgesia effects.

Knee osteoarthritis (KOA) is a chronic degenerative joint disease marked by pain, cartilage degradation, and limited mobility. Existing treatments remain suboptimal due to limited efficacy and adverse effects, highlighting the urgent need for safer, mechanism-based therapies. Electroacupuncture (EA) has demonstrated clinical benefits in KOA, yet its underlying molecular mechanisms remain unclear. A KOA rat model was established via intra-articular injection of monosodium iodoacetate (MIA). EA was applied at Dubi (ST35) and Neixiyan (EX-LE5) acupoints. We assessed the effect of EA on nociceptive behavior in rats with KOA using von Frey filament testing, weight-bearing asymmetry measurements, and spontaneous pain assays. Cartilage degeneration was analyzed via toluidine blue staining, while immunofluorescence staining quantified protein expression levels in cartilage and dorsal root ganglia (DRG). Inhibitor and agonist injections were employed to evaluate the specific involvement of the NGF/TrkA pathway in EA-mediated effects. EA significantly reduced mechanical allodynia ( < 0.001), weight-bearing asymmetry ( < 0.001), spontaneous pain ( < 0.001). EA decreased macroscopic chondropathy score ( < 0.01) and cartilage degeneration score ( < 0.001). EA inhibited MMP13 expression ( < 0.05), suppressed NGF ( < 0.001) and TrkA ( < 0.05) expression, decreased PGP9.5 overexpression ( < 0.05), and downregulated pro-inflammatory cytokines IL-1β ( < 0.01) and TNF-α ( < 0.01). Pharmacological inhibition of NGF/TrkA mimicked EA's effects, while activation of this pathway counteracted its analgesia. EA selectively downregulated TrkA in CGRP ( < 0.01), but not IB4 ( > 0.05) or NF200 ( > 0.05) DRG neurons subtypes. Our results demonstrate that EA alleviates KOA, possibly via inhibiting NGF/TrkA pathway activation in knee joints and reducing TrkA expression in CGRP sensory neurons, supporting the therapeutic potential of EA for KOA.

Accumulating evidence supports an association between chronic pain and psychological disorders, a connection that seems to be bidirectional. Treating both the pain and psychological conditions together is essential for effective treatment outcomes. Acupuncture is a somatosensory-guided mind–body therapy that can tackle the multidimensional nature of pain with fewer or no serious adverse effects. In this review, we discuss the use of acupuncture in some conditions with a high incidence of psychological disorders caused by chronic pain: headache, musculoskeletal pain, low back pain, and cancer pain, focusing on the effect and potential mechanisms of acupuncture. Overall clinical studies indicated that acupuncture might effectively contribute to management of psychological disorders caused by chronic pain. Mechanistic studies showed that acupuncture significantly alleviated such psychological disorders by regulating the activity of amygdala and insula, and regulating functional connectivity of insular and limbic regions/medial prefrontal cortex in humans and the corresponding animal models. In addition, 5-HT in the dorsal raphe nucleus, opioid receptors in the cingulate cortex, and plasma met-enkephalin are involved in acupuncture relief of pain and psychological symptoms. Substantial evidences from animal and human research support a beneficial effect of acupuncture in psychological disorders caused by chronic pain.

Reliable animal models are invaluable for monitoring the extent of pollution in the aquatic environment. In this study, we demonstrated the potential of huORFZ, a novel transgenic zebrafish line that harbors a human upstream open reading frame of the chop gene fused with GFP reporter, as an animal model for monitoring environmental pollutants and stress-related cellular processes. When huORFZ embryos were kept under normal condition, no leaked GFP signal could be detected. When treated with hazardous chemicals, including heavy metals and endocrine-disrupting chemicals near their sublethal concentrations (LC50), huORFZ embryos exhibited different tissue-specific GFP expression patterns. For further analysis, copper (Cu2+), cadmium (Cd2+) and Chlorpyrifos were applied. Cu2+ triggered GFP responses in skin and muscle, whereas Cd2+ treatment triggered GFP responses in skin, olfactory epithelium and pronephric ducts. Moreover, fluorescence intensity, as exhibited by huORFZ embryos, was dose-dependent. After surviving treated embryos were returned to normal condition, survival rates, as well as TUNEL signals, returned to pretreatment levels with no significant morphological defects observed. Such results indicated the reversibility of treatment conditions used in this study, as long as embryos survived such conditions. Notably, GFP signals decreased along with recovery, suggesting that GFP signaling of huORFZ embryos likely reflected the overall physiological condition of the individual. To examine the performance of the huORFZ line under real-world conditions, we placed huORFZ embryos in different river water samples. We found that the huORFZ embryos correctly detected the presence of various kinds of pollutants. Based on these findings, we concluded that such uORFchop-based system can be integrated into a first-line water alarm system monitoring the discharge of hazardous pollutants.

Knee osteoarthritis (KOA) is a highly prevalent, chronic joint disorder, with chronic pain as its typical symptom. Although studies have shown that an activated peripheral CB2 receptor can reduce acute pain, whether the CB2 receptor is involved in electroacupuncture (EA) inhibiting chronic pain and the involved mechanism remains unclear. The aim of this study was to investigate whether EA may strengthen peripheral CB2 receptor-inhibited chronic pain in a mouse model of KOA. KOA was induced by intra-articular injection of monosodium iodoacetate (MIA) into the left knee joint of mice. Thermal hyperalgesia was tested with the hot plate test, and mechanical allodynia was quantified using von Frey filaments. The expression of CB2 receptor and IL-1β were quantified by using immunofluorescence labeling. EA treatment at 2 Hz+1 mA significantly increased the expression of CB2 receptor in fibroblasts and decreased the expression of IL-1β in the menisci compared with that in the KOA group. However, EA had no effect on the expression of IL-1β in CB2 mice. At 2 Hz+1 mA, EA significantly increased mechanical threshold, thermal latency, and weight borne after KOA modeling. However, knockout of the CB2 receptor blocked these effects of EA. After 2 Hz+1 mA treatment, EA significantly reduced the Osteoarthritis Research Society International (OARSI) score after KOA modeling. However, EA had no significant effect on the OARSI score in CB2 mice. EA reduced the expression of IL-1β by activating the CB2 receptor, thus inhibiting the chronic pain in the mouse model of KOA.