{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:21:46Z","timestamp":1792801306053,"version":"4.5.0"},"reference-count":40,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T00:00:00Z","timestamp":1683763200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"DMR-112-174","award":["DMR-112-174"],"award-info":[{"award-number":["DMR-112-174"]}]},{"name":"EDAHP108031","award":["EDAHP108031"],"award-info":[{"award-number":["EDAHP108031"]}]},{"name":"EDAHP109033","award":["EDAHP109033"],"award-info":[{"award-number":["EDAHP109033"]}]},{"name":"EDAHP110026","award":["EDAHP110026"],"award-info":[{"award-number":["EDAHP110026"]}]},{"name":"EDAHP111037","award":["EDAHP111037"],"award-info":[{"award-number":["EDAHP111037"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>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\u2019s 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.<\/jats:p>","DOI":"10.3390\/life13051160","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T03:22:19Z","timestamp":1683775339000},"page":"1160","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Electroacupuncture Attenuates Fibromyalgia Pain via Toll-like Receptor 4 in the Mouse Brain"],"prefix":"10.3390","volume":"13","author":[{"given":"Po-Chih","family":"Lai","sequence":"first","affiliation":[{"name":"College of Chinese Medicine, Graduate Institute of Acupuncture Science, China Medical University, Taichung 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chia-Ming","family":"Yen","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 42743, Taiwan"},{"name":"School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming-Chia","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, E-DA Hospital, College of Medicine, I-Shou University, Kaohsiung 82445, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8756-5113","authenticated-orcid":false,"given":"Yung-Hsiang","family":"Chen","sequence":"additional","affiliation":[{"name":"Graduate Institute of Integrated Medicine, China Medical University, Taichung 40402, Taiwan"},{"name":"Department of Psychology, College of Medical and Health Science, Asia University, Taichung 41305, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsien-Yin","family":"Liao","sequence":"additional","affiliation":[{"name":"College of Chinese Medicine, School of Post-Baccalaureate Chinese Medicine, China Medical University, Taichung 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Wei","family":"Huang","sequence":"additional","affiliation":[{"name":"Emergency and Critical Care Center, E-Da Hospital, Kaohsiung 80708, Taiwan"},{"name":"Department of Nursing, School of Nursing, Fooyin University, Kaohsiung 83102, Taiwan"},{"name":"School of Medicine, College of Medicine, I-Shou University, Kaohsiung 824, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7204-8837","authenticated-orcid":false,"given":"Yi-Wen","family":"Lin","sequence":"additional","affiliation":[{"name":"College of Chinese Medicine, Graduate Institute of Acupuncture Science, China Medical University, Taichung 40402, Taiwan"},{"name":"Chinese Medicine Research Center, China Medical University, Taichung 40402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"ITC33","DOI":"10.7326\/AITC202003030","article-title":"Fibromyalgia","volume":"172","author":"Bair","year":"2020","journal-title":"Ann. Intern. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1002\/art.1780380104","article-title":"The prevalence and characteristics of fibromyalgia in the general population","volume":"38","author":"Wolfe","year":"1995","journal-title":"Arthritis Rheum."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.rbr.2016.10.004","article-title":"Prevalence of fibromyalgia: Literature review update","volume":"57","author":"Marques","year":"2017","journal-title":"Rev. Bras. Reumatol. Engl. Ed."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1155\/2013\/918216","article-title":"2012 Canadian Guidelines for the diagnosis and management of fibromyalgia syndrome: Executive summary","volume":"18","author":"Fitzcharles","year":"2013","journal-title":"Pain. Res. Manag."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"47","DOI":"10.20452\/pamw.3877","article-title":"Management of fibromyalgia: Practical guides from recent evidence-based guidelines","volume":"127","author":"Hauser","year":"2017","journal-title":"Pol. Arch. Intern. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1016\/j.apmr.2020.06.019","article-title":"Effectiveness of Exercise on Fatigue and Sleep Quality in Fibromyalgia: A Systematic Review and Meta-analysis of Randomized Trials","volume":"102","author":"Russell","year":"2021","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"R121","DOI":"10.1186\/ar2010","article-title":"Psychological pain treatment in fibromyalgia syndrome: Efficacy of operant behavioural and cognitive behavioural treatments","volume":"8","author":"Thieme","year":"2006","journal-title":"Arthritis Res. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/S0254-6272(15)30037-6","article-title":"Efficacy of acupuncture on fibromyalgia syndrome: A meta-analysis","volume":"34","author":"Bai","year":"2014","journal-title":"J. Tradit. Chin. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1002\/1097-4598(200101)24:1<37::AID-MUS4>3.0.CO;2-8","article-title":"Unilateral intramuscular injections of acidic saline produce a bilateral, long-lasting hyperalgesia","volume":"24","author":"Sluka","year":"2001","journal-title":"Muscle Nerve"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1136\/annrheumdis-2020-218329","article-title":"Activation of acid-sensing ion channel 3 by lysophosphatidylcholine 16:0 mediates psychological stress-induced fibromyalgia-like pain","volume":"79","author":"Hung","year":"2020","journal-title":"Ann. Rheum. Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.neulet.2010.01.080","article-title":"Absence of morphine analgesia and its underlying descending serotonergic activation in an experimental mouse model of fibromyalgia","volume":"472","author":"Nishiyori","year":"2010","journal-title":"Neurosci. Lett."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1016\/j.bbi.2020.06.033","article-title":"Transient receptor potential V1(TRPV1) modulates the therapeutic effects for comorbidity of pain and depression: The common molecular implication for electroacupuncture and omega-3 polyunsaturated fatty acids","volume":"89","author":"Lin","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/ni.1863","article-title":"The role of pattern-recognition receptors in innate immunity: Update on Toll-like receptors","volume":"11","author":"Kawai","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kuzmich, N.N., Sivak, K.V., Chubarev, V.N., Porozov, Y.B., Savateeva-Lyubimova, T.N., and Peri, F. (2017). TLR4 Signaling Pathway Modulators as Potential Therapeutics in Inflammation and Sepsis. Vaccines, 5.","DOI":"10.3390\/vaccines5040034"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1016\/j.bbrc.2009.08.062","article-title":"Toll-like receptors and innate immunity","volume":"388","author":"Kumar","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_16","first-page":"1853","article-title":"Association between toll-like receptor 4 expression and symptoms of major depressive disorder","volume":"11","author":"Wu","year":"2015","journal-title":"Neuropsychiatr. Dis. Treat."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.phrs.2016.11.019","article-title":"Therapeutic implications of toll-like receptors in peripheral neuropathic pain","volume":"115","author":"Thakur","year":"2017","journal-title":"Pharmacol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.brainresbull.2019.03.015","article-title":"Role of toll-like receptor 4 in the regulation of the cell death pathway and neuroinflammation","volume":"148","author":"Li","year":"2019","journal-title":"Brain Res. Bull."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8285","DOI":"10.1523\/JNEUROSCI.0976-10.2010","article-title":"Pivotal role of TLR4 receptors in alcohol-induced neuroinflammation and brain damage","volume":"30","author":"Blanco","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1523\/JNEUROSCI.4268-04.2005","article-title":"Toll-like receptor 4 on nonhematopoietic cells sustains CNS inflammation during endotoxemia, independent of systemic cytokines","volume":"25","author":"Chakravarty","year":"2005","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"42531","DOI":"10.1038\/srep42531","article-title":"Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice","volume":"7","author":"Liao","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"82","DOI":"10.51248\/.v41i1.538","article-title":"Electromyography changes in assessment of functional status of muscles in subjects with knee-osteoarthritis undergoing low level laser therapy","volume":"41","author":"Kumar","year":"2021","journal-title":"Biomedicine"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Li, Y., Yin, C., Li, X., Liu, B., Wang, J., Zheng, X., Shao, X., Liang, Y., Du, J., and Fang, J. (2019). Electroacupuncture Alleviates Paclitaxel-Induced Peripheral Neuropathic Pain in Rats via Suppressing TLR4 Signaling and TRPV1 Upregulation in Sensory Neurons. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20235917"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0166-2236(02)00006-1","article-title":"Acupuncture: Neuropeptide release produced by electrical stimulation of different frequencies","volume":"26","author":"Han","year":"2003","journal-title":"Trends Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1038\/nm.3479","article-title":"Dopamine mediates vagal modulation of the immune system by electroacupuncture","volume":"20","author":"Yehia","year":"2014","journal-title":"Nat. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1038\/nn.2562","article-title":"Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture","volume":"13","author":"Goldman","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/s41586-021-04001-4","article-title":"A neuroanatomical basis for electroacupuncture to drive the vagal-adrenal axis","volume":"598","author":"Liu","year":"2021","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1016\/j.genhosppsych.2008.12.006","article-title":"Pharmacotherapy of chronic pain: A synthesis of recommendations from systematic reviews","volume":"31","author":"Kroenke","year":"2009","journal-title":"Gen. Hosp. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1136\/acupmed-2015-010950","article-title":"Acupuncture for fibromyalgia in primary care: A randomised controlled trial","volume":"34","author":"Vas","year":"2016","journal-title":"Acupunct. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1093\/rheumatology\/kep439","article-title":"Efficacy of acupuncture in fibromyalgia syndrome--a systematic review with a meta-analysis of controlled clinical trials","volume":"49","author":"Langhorst","year":"2010","journal-title":"Rheumatology"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Lottering, B., and Lin, Y.W. (2021). TRPV1 Responses in the Cerebellum Lobules VI, VII, VIII Using Electroacupuncture Treatment for Chronic Pain and Depression Comorbidity in a Murine Model. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22095028"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.yexcr.2018.05.012","article-title":"Glycyrrhizin ameliorates inflammatory pain by inhibiting microglial activation-mediated inflammatory response via blockage of the HMGB1-TLR4-NF-kB pathway","volume":"369","author":"Sun","year":"2018","journal-title":"Exp. Cell. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1007\/s10571-015-0228-0","article-title":"Ligustilide Ameliorates Inflammatory Pain and Inhibits TLR4 Upregulation in Spinal Astrocytes Following Complete Freund\u2019s Adjuvant Peripheral Injection","volume":"36","author":"Qian","year":"2016","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Li, X.Q., Zhang, Z.L., Tan, W.F., Sun, X.J., and Ma, H. (2016). Down-Regulation of CXCL12\/CXCR4 Expression Alleviates Ischemia-Reperfusion-Induced Inflammatory Pain via Inhibiting Glial TLR4 Activation in the Spinal Cord. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0163807"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1186\/s13020-021-00451-0","article-title":"Electroacupuncture reduces cold stress-induced pain through microglial inactivation and transient receptor potential V1 in mice","volume":"16","author":"Liao","year":"2021","journal-title":"Chin. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/j.biopha.2018.07.116","article-title":"Analgesic effects of TLR4\/NF-kappaB signaling pathway inhibition on chronic neuropathic pain in rats following chronic constriction injury of the sciatic nerve","volume":"107","author":"Xu","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"5238730","DOI":"10.1155\/2016\/5238730","article-title":"Blockade of Toll-Like Receptors (TLR2, TLR4) Attenuates Pain and Potentiates Buprenorphine Analgesia in a Rat Neuropathic Pain Model","volume":"2016","author":"Jurga","year":"2016","journal-title":"Neural Plast."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5856","DOI":"10.1073\/pnas.0501634102","article-title":"The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy","volume":"102","author":"Tanga","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.ejphar.2011.11.037","article-title":"Effects of intrathecal epigallocatechin gallate, an inhibitor of Toll-like receptor 4, on chronic neuropathic pain in rats","volume":"676","author":"Kuang","year":"2012","journal-title":"Eur. J. Pharmacol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1038\/nrrheum.2013.160","article-title":"Role of cytokines in intervertebral disc degeneration: Pain and disc content","volume":"10","author":"Risbud","year":"2014","journal-title":"Nat. Rev. Rheumatol."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/5\/1160\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:32:43Z","timestamp":1760124763000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/13\/5\/1160"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,11]]},"references-count":40,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["life13051160"],"URL":"https:\/\/doi.org\/10.3390\/life13051160","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,11]]}}}