Hsin-Cheng Hsu

Fibromyalgia is a widespread, chronic musculoskeletal pain syndrome that primarily afflicts adult females (approximately 90% of cases), with peak incidence between age 30 and 50 years. Overall prev...

Background: Fibromyalgia is a chronic disease that predominantly affects women and lasts over several months, causing problems both for individuals and society. While several studies have demonstrated the potential of electroacupuncture (EA) to alleviate fibromyalgia pain in mice, further research is needed to investigate its underlying mechanisms. Programmed cell death ligand 1 (PD-L1)/PD-1 were first identified to be involved in cancer immunotherapy, and their application to pain management has not been yet investigated. Methods: In this study, we aimed to explore the mechanism underlying the action of PD-L1 on the PD-1 pathway in a mouse model of fibromyalgia. Results: We established such a mouse model using intermittent cold stress (ICS) and confirmed mechanical (D4: 2.02 ± 0.13 g, n = 9) and thermal (D4: 4.28 ± 0.21 s, n = 9) hyperalgesia. We found that EA, intracerebral ventricle (ICV) PD-L1 injection, and transient receptor potential vanilloid 1 (Trpv1) knockout effectively counteracted hyperalgesia. We observed low PD-1 expression in the cerebellum of fibromyalgia mice but increased expression of TRPV1 and pain-related kinases. These phenomena could be further reversed by EA, ICV PD-L1 injection, and Trpv1 knockout. To confirm that these effects were caused by PD-L1 release, we added PD-L1-neutralizing antibodies to the EA and PD-L1 treatment. The analgesic effects and EA and PD-L1 mechanisms were inhibited. Conclusions: Our results elucidate the role of the PD-L1/PD-1 pathway in EA treatment of fibromyalgia and reveal its potential value for fibromyalgia management.

Traumatic brain injury (TBI) refers to a brain injury caused by a traumatic impact. Depending on severity, TBI can be classified as mild, which may temporarily affect brain function, or severe, which can cause long-term complications such as headaches, speech disorders, mood changes, anxiety, and depression. At present, common treatments for TBI include anti-anxiety drugs, anticonvulsants, antidepressants, and muscle relaxants. However, the use of electroacupuncture (EA) for TBI and its molecular mechanisms remain poorly studied. To address this research gap, this study examined the influence of EA on neuroinflammation, adiponectin, and transient receptor potential vanilloid 1 (TRPV1) pathways in a mouse model of TBI. TBI was induced using automatic gravity impact. Molecular analyses confirmed that TBI causes a neuroinflammatory response in the medial prefrontal cortex. TBI model mice showed decreases in the adiponectin receptor 1 (AdipoR1) and TRPV1 signaling pathways, leading to comorbid depression. Next, we demonstrated that EA or Trpv1−/− reduced levels of astrocytes, microglia, and their signaling mediators high mobility group box 1 and s100 calcium-binding protein B. Notably, EA or Trpv1−/− further increased AdipoR1–APPL1 and these effects were downstream to the AMPK/PPAR/SIRT1 pathway. Similar results were observed in the TRPV1 signaling pathway. Taken together, these findings indicate that EA effectively treats TBI by reducing neuroinflammation and activating the AdipoR1 and TRPV1 pathways, providing important directions and applications for future clinical research.

Background: Fibromyalgia is a chronic disease that predominantly affects women and lasts over several months, causing problems both to individuals and society. While several studies have demonstrated the potential of electroacupuncture (EA) to alleviate fibromyalgia pain in mice, further research is needed to investigate its underlying mechanisms. Programmed cell death ligand-1 (PD-L1)/PD-1 was first identified to be involved in cancer immunotherapy, but its application to pain management has not been yet investigated. Methods: This study aimed to explore the mechanism underlying action of PD-L1 on PD-1 pathway in a mouse model of fibromyalgia. Results: We established such a mouse model using intermittent cold stress (ICS) and confirmed mechanical (D4: 2.02 ± 0.13 g, n = 9) and thermal (D4: 4.28 ± 0.21 s, n = 9) hyperalgesia. We found that EA, intracerebral ventricle (ICV) PD-L1 injection, or transient receptor potential vanilloid 1 (Trpv1) knockout effectively counteracted hyperalgesia. We observed low PD-1 expression in the cerebellum of fibromyalgia mice but increased expression of TRPV1 and pain-related kinases. These phenomena could be further reversed by EA, ICV PD-L1 injection, and Trpv1 knockout. To confirm that these effects were caused by PD-L1 release, we added PD-L1 neutralizing antibodies to the EA and PD-L1 treatment. The analgesic effects and EA and PD-L1 mechanisms were inhibited. Conclusions: Our results elucidate the role of the PD-L1/PD-1 pathway in EA treatment of fibromyalgia and reveal its potential value for fibromyalgia.

Fibromyalgia (FM) is characterized by widespread musculoskeletal pain and tenderness, cognitive dysfunction, fatigue, and insomnia. Electroacupuncture (EA) has documented efficacy against FM-associated pain, while cannabinoid receptor 1 (CB1) plays a critical role in endogenous analgesia. Herein, we examined whether pain relief initiated by EA was linked with differing cerebellar CB1 levels and signaling in an intermittent cold stress (ICS) mouse model of FM. FM-like hyperalgesia and recovery were assessed by measuring mechanical and thermal nociceptive thresholds. Compared to control mice, ICS-induced FM-model mice exhibited a significantly reduced mechanical withdrawal threshold (2.3 ± 0.1 g) and shorter thermal withdrawal latency (4.0 ± 0.5 s), indicative of mechanical and thermal hyperalgesia. Both conditions were reversed by 2 Hz EA but not sham EA. Hyperalgesia was associated with reduced CB1 receptor expression and the enhanced activity of multiple nociceptive signaling pathways (PKA, PI3K, Akt, mTOR, ERK, and NF-kB) in the mouse cerebellum. The 2 Hz EA treatment reliably reversed these abnormalities, while the sham EA treatment did not. Intracerebroventricular injection of the CB1 agonist anandamide (AEA) recapitulated the effects of EA on pain thresholds, while the analgesic effects of EA were blocked by the CB1 antagonist AM251. Precise chemogenetic stimulation at the paraventricular nucleus (PVN) of the hypothalamus reliably induced FM pain. Chemogenetic inhibition at the PVN diminished FM through the CB1 pathway in the cerebellum. Our findings suggest that dysregulation of CB1 expression and aberrant hyperactivity of nociceptive signaling pathways in the cerebellum contribute to the etiology of FM and that the upregulation of CB1 signaling mediates the analgesic efficacy of EA.

Background/Objectives: Fibromyalgia causes chronic long-term pain, with symptoms lasting for months to years. Given the lack of evidence-based methods for diagnosing and assessing fibromyalgia, it ranks among the most difficult chronic pain conditions to treat. Programmed cell death ligand 1 (PD-L1) can inhibit acute and chronic pain transmission by inhibiting neuronal ion channels. Methods: Here, we aimed to explore the analgesic efficacy and mechanism of PD-L1/PD1 in an intermittent cold stress-induced fibromyalgia pain mouse model. Results: Von Frey and Hargreaves tests were performed, showing that the mouse model exhibited mechanical (day 4: 2.08 ± 0.13 g, n = 9) and thermal hyperalgesia (day 4: 3.93 ± 0.45 s, n = 9). Electroacupuncture (EA) or intraventricular PD-L1 injection effectively alleviated the nociceptive response and led to low PD-1 levels in the mouse dorsal root ganglia, spinal cord, thalamus, somatosensory cortex, and cerebellum, as measured through Western blots. In contrast, the pain-related kinase levels increased after fibromyalgia induction; these effects were reversed by EA and PD-L1 via the inhibition of microglia/astrocytes and Toll-like receptor 4. Conclusions: Our results show that EA can treat fibromyalgia pain in mice through effects on the PD-L1/PD1 pathway, indicating its potential as a therapeutic target in fibromyalgia.

Background/Objectives: Fibromyalgia is a chronic pain syndrome with unclear etiology, meaning that it is difficult to treat effectively. The stimulation of cannabinoid receptor 1 (CB1) suppresses neuronal excitability and synaptic transmission in nociceptive pathways via reducing activity in the calcium channel and promoting the opening of the potassium channel. Methods: In this study, we examined whether CB1 activity contributes to the antinociceptive efficacy of electroacupuncture (EA) in a mouse fibromyalgia (FM) pain model established using intermittent cold stress (ICS). The model mice demonstrated both mechanical and thermal hyperalgesia measured using the von Frey and Hargreaves tests, respectively. Results: Electroacupuncture effectively reduced both forms of hyperalgesia and enhanced CB1 expression in the dorsal root ganglia, spinal cord, hypothalamus, and periaqueductal gray. In addition, EA attenuated the fibromyalgia-associated reactive transformation of microglia and astrocytes and the activation of the pain-related TLR4–MyD88–TRAF6 signaling pathway. The effects of ICS were also mitigated by the deletion of Trpv1, the gene encoding the transient receptor potential cation channel TRPV1 (capsaicin channel) implicated in nociceptive and inflammatory signaling. Further, the antinociceptive efficacy of EA was partially recapitulated by the acupoint injection of a CB1 agonist and abolished by the injection of a CB1 antagonist, suggesting that activating CB1 is essential for this therapeutic effect. Conclusions: Electroacupuncture can effectively alleviate mechanical and thermal hyperalgesia in a mouse model affected by fibromyalgia pain by activating the CB1 pathway, highlighting the therapeutic potential of CB1 agonism as a therapeutic strategy.

Fibromyalgia (FM) is a widespread systemic pain disorder often accompanied by symptoms such as insomnia, mania, obesity, and depression. FM is difficult to diagnose and, therefore, cannot be effectively treated with current medical approaches. After prolonged suffering, FM patients frequently seek help from chronic pain physicians and psychiatrists. Eicosapentaenoic acid (EPA), derived from fish oil, is a common nutritional therapy for pain. While EPA is a documented fatty acid for depression treatment, its role in FM management is less established. In this study, we investigated the effects of EPA on FM pain and its potential mechanisms involving microglia/astrocytes and toll-like receptor 4 (TLR4) pathways in the cerebellum of mice. We found that intermittent cold stress (ICS) effectively induced FM-like pain in mice. Pain was evaluated using von Frey and Hargraves' tests to assess mechanical (2.01 ± 0.11 g) and thermal (4.09 ± 0.34 s) sensitivity. Nociceptive responses were alleviated by oral EPA administration (3.68 ± 0.13 g and 7.89 ± 0.3 s). EPA levels were lower in FM mice but increased following oral intake. Our findings revealed elevated levels of microglia/astrocyte markers and neurotransmitters such as HMGB1 and S100B in the cerebellum 5-7 (CB5-7) of FM mice. Similarly, TLR4 and related nociceptive signals were upregulated in the FM group. Notably, oral EPA effectively reduced these pain-related substances in CB5-7. Our results suggest that EPA can treat FM by modulating microglia/astrocyte activity and TLR4 signaling, highlighting its potential as a therapeutic target in FM management.

Fibromyalgia is a disease difficult to cure that causes chronic long-term pain, with symptoms lasting for months to years. Given the lack of evidence-based diagnosis and assessment methods for fibromyalgia, it ranks among the most difficult chronic pain conditions to treat. Programmed cell death ligand 1 (PD-L1) can inhibit acute and chronic pain transmission by inhibiting neuronal ion channels. Here, we aimed to explore the analgesic efficacy and mechanism of PD-L1/PD1 in a mouse fibromyalgia pain model. We used intermit-tent cold stress (ICS) to induce fibromyalgia in mice, this model was characterized by von Frey and Har-greaves’ tests. ICS-induced fibromyalgia pain mouse model exhibited mechanical and thermal hyperalgesia. Electroacupuncture (EA) or intraventricular PD-L1 injection effectively alleviated the nociceptive response and exhibited low PD-1 levels in the mouse dorsal root ganglia, spinal cord, thalamus, somatosensory cortex, and cerebellum. In contrast, pain-related kinase levels increased after fibromyalgia induction, and these effects was reversed by EA or PD-L1 via inhibition of microglia/astrocytes and toll-like receptor 4. Our results show that EA can treat fibromyalgia pain in mice through the PD-L1/PD1 pathway, indicating its therapeutic po-tential as a target in fibromyalgia.