{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,5]],"date-time":"2026-05-05T03:56:42Z","timestamp":1777953402137,"version":"3.51.4"},"reference-count":38,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T00:00:00Z","timestamp":1758067200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Chinese Medicine Research Center, China Medical University","award":["NSTC 113-2314-B-039-047"],"award-info":[{"award-number":["NSTC 113-2314-B-039-047"]}]},{"name":"Chinese Medicine Research Center, China Medical University","award":["CMUHCH-DMR-113-025"],"award-info":[{"award-number":["CMUHCH-DMR-113-025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Life"],"abstract":"<jats:p>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 \u00b1 0.1 g) and shorter thermal withdrawal latency (4.0 \u00b1 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.<\/jats:p>","DOI":"10.3390\/life15091458","type":"journal-article","created":{"date-parts":[[2025,9,17]],"date-time":"2025-09-17T14:10:19Z","timestamp":1758118219000},"page":"1458","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Chemogenetic Modulation of Electroacupuncture Analgesia in a Mouse Intermittent Cold Stress-Induced Fibromyalgia Model by Activating Cerebellum Cannabinoid Receptor 1 Expression and Signaling"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6245-9023","authenticated-orcid":false,"given":"I-Han","family":"Hsiao","sequence":"first","affiliation":[{"name":"School of Medicine, College of Medicine, China Medical University, Taichung 404328, Taiwan"},{"name":"Department of Neurosurgery, China Medical University Hospital, Taichung 404332, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-Chia","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9150-0339","authenticated-orcid":false,"given":"Hsin-Cheng","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Traditional Chinese Medicine, China Medical University Hsinchu Hospital, Hsinchu 302233, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6787-2215","authenticated-orcid":false,"given":"Younbyoung","family":"Chae","sequence":"additional","affiliation":[{"name":"Acupuncture and Meridian Science Research Center, Kyung Hee University, Seoul 02453, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi-Kai","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, E-DA Hospital, I-Shou University, Kaohsiung 82445, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7204-8837","authenticated-orcid":false,"given":"Yi-Wen","family":"Lin","sequence":"additional","affiliation":[{"name":"Graduate Institute of Acupuncture Science, College of Chinese Medicine, China Medical University, Taichung 404328, Taiwan"},{"name":"Chinese Medicine Research Center, China Medical University, Taichung 404328, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1016\/j.bbi.2019.12.020","article-title":"Peripheral immune aberrations in fibromyalgia: A systematic review, meta-analysis and meta-regression","volume":"87","author":"Borras","year":"2020","journal-title":"Brain Behav. Immun."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"413","DOI":"10.5114\/reum.2022.123671","article-title":"Fibromyalgia syndrome: Epidemiology, diagnosis and treatment","volume":"60","author":"Kocyigit","year":"2022","journal-title":"Reumatologia"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1002\/art.41170","article-title":"Transcutaneous Electrical Nerve Stimulation Reduces Movement-Evoked Pain and Fatigue: A Randomized, Controlled Trial","volume":"72","author":"Dailey","year":"2020","journal-title":"Arthritis Rheumatol."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sagy, I., Bar-Lev Schleider, L., Abu-Shakra, M., and Novack, V. (2019). Safety and Efficacy of Medical Cannabis in Fibromyalgia. J. Clin. Med., 8.","DOI":"10.3390\/jcm8060807"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.bbi.2018.09.018","article-title":"Brain glial activation in fibromyalgia\u2014A multi-site positron emission tomography investigation","volume":"75","author":"Albrecht","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Gyorfi, M., Rupp, A., and Abd-Elsayed, A. (2022). Fibromyalgia Pathophysiology. Biomedicines, 10.","DOI":"10.3390\/biomedicines10123070"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1097\/j.pain.0000000000002309","article-title":"The translocator protein gene is associated with endogenous pain modulation and the balance between glutamate and gamma-aminobutyric acid in fibromyalgia and healthy subjects: A multimodal neuroimaging study","volume":"163","author":"Fanton","year":"2022","journal-title":"Pain"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"L\u00f6fgren, M., Sandstrom, A., Bileviciute-Ljungar, I., Mannerkorpi, K., Gerdle, B., Ernberg, M., Fransson, P., and Kosek, E. (2023). The effects of a 15-week physical exercise intervention on pain modulation in fibromyalgia: Increased pain-related processing within the cortico-striatal- occipital networks, but no improvement of exercise-induced hypoalgesia. Neurobiol. Pain, 13.","DOI":"10.1016\/j.ynpai.2023.100114"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbi.2014.06.007","article-title":"The endocannabinoid system modulates stress, emotionality, and inflammation","volume":"42","author":"Crowe","year":"2014","journal-title":"Brain Behav. Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.bbi.2015.06.002","article-title":"Endocannabinoids drive the acquisition of an alternative phenotype in microglia","volume":"49","author":"Mecha","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Kendall, D.A., and Yudowski, G.A. (2016). Cannabinoid Receptors in the Central Nervous System: Their Signaling and Roles in Disease. Front. Cell Neurosci., 10.","DOI":"10.3389\/fncel.2016.00294"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12504","DOI":"10.1002\/cam4.5962","article-title":"Acupuncture for the prevention of chemotherapy-induced nausea and vomiting in cancer patients: A systematic review and meta-analysis","volume":"12","author":"Yan","year":"2023","journal-title":"Cancer Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1111\/adj.12926","article-title":"Management strategies for adult patients with dental anxiety in the dental clinic: A systematic review","volume":"67","author":"Hoffmann","year":"2022","journal-title":"Aust. Dent. J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wang, M., Liu, W., Ge, J., and Liu, S. (2023). The immunomodulatory mechanisms for acupuncture practice. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1147718"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hsiao, I.H., Liao, H.Y., Cheng, C.M., Yen, C.M., and Lin, Y.W. (2022). Paper-Based Detection Device for Microenvironment Examination: Measuring Neurotransmitters and Cytokines in the Mice Acupoint. Cells, 11.","DOI":"10.3390\/cells11182869"},{"key":"ref_16","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_17","doi-asserted-by":"crossref","unstructured":"Liao, H.Y., Hsieh, C.L., Huang, C.P., and Lin, Y.W. (2017). Electroacupuncture Attenuates CFA-induced Inflammatory Pain by suppressing Nav1.8 through S100B, TRPV1, Opioid, and Adenosine Pathways in Mice. Sci. Rep., 7.","DOI":"10.1038\/srep42531"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Liao, H.Y., Hsieh, C.L., Huang, C.P., and Lin, Y.W. (2017). Electroacupuncture Attenuates Induction of Inflammatory Pain by Regulating Opioid and Adenosine Pathways in Mice. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-16031-y"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2147\/JPR.S351320","article-title":"Effect of Acupuncture on Pain, Fatigue, Sleep, Physical Function, Stiffness, Well-Being, and Safety in Fibromyalgia: A Systematic Review and Meta-Analysis","volume":"15","author":"Zheng","year":"2022","journal-title":"J. Pain Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"9869250","DOI":"10.1155\/2020\/9869250","article-title":"Acupuncture for Fibromyalgia: An Open-Label Pragmatic Study on Effects on Disease Severity, Neuropathic Pain Features, and Pain Catastrophizing","volume":"2020","author":"Beci","year":"2020","journal-title":"Evid. Based Complement. Alternat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1007\/s12035-014-8790-x","article-title":"IL-10 cytokine released from M2 macrophages is crucial for analgesic and anti-inflammatory effects of acupuncture in a model of inflammatory muscle pain","volume":"51","author":"Bobinski","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhou, X., Zhang, Y.C., Lu, K.Q., Xiao, R., Tang, W.C., and Wang, F. (2024). The Role of p38 Mitogen-Activated Protein Kinase-Mediated F-Actin in the Acupuncture-Induced Mitigation of Inflammatory Pain in Arthritic Rats. Brain Sci., 14.","DOI":"10.3390\/brainsci14040380"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"13","DOI":"10.37796\/2211-8039.1174","article-title":"Inflammation, oxidative stress, insulin resistance, and hypertension as mediators for adverse effects of obesity on the brain: A review","volume":"11","author":"Ghowsi","year":"2021","journal-title":"Biomedicine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"104645","DOI":"10.1016\/j.jpain.2024.104645","article-title":"Acupuncture Modulation of Chronic Neuropathic Pain and Its Association with Brain Functional Properties","volume":"25","author":"Wei","year":"2024","journal-title":"J. Pain"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e1200","DOI":"10.1097\/PR9.0000000000001200","article-title":"The analgesic effect of acupuncture in neuropathic pain: Regulatory mechanisms of DNA methylation in the brain","volume":"9","author":"Jang","year":"2024","journal-title":"Pain Rep."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Huo, M., Zhang, Q., Si, Y., Zhang, Y., Chang, H., Zhou, M., Zhang, D., and Fang, Y. (2024). The role of purinergic signaling in acupuncture-mediated relief of neuropathic and inflammatory pain. Purinergic Signalling, Springer.","DOI":"10.1007\/s11302-024-09985-y"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1016\/j.bbi.2024.10.028","article-title":"Chemogenetic targeting TRPV1 in obesity-induced depression: Unveiling therapeutic potential of eicosapentaenoic acid and acupuncture","volume":"123","author":"Lin","year":"2025","journal-title":"Brain Behav. Immun."},{"key":"ref_28","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_29","doi-asserted-by":"crossref","unstructured":"Anh, D.T.N., and Lin, Y.W. (2024). Electroacupuncture Mitigates TRPV1 Overexpression in the Central Nervous System Associated with Fibromyalgia in Mice. Life, 14.","DOI":"10.3390\/life14121605"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.neucli.2021.03.002","article-title":"Repetitive transcranial magnetic stimulation (rTMS) versus transcranial direct current stimulation (tDCS) in the management of patients with fibromyalgia: A randomized controlled trial","volume":"51","author":"Forogh","year":"2021","journal-title":"Neurophysiol. Clin."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e3072","DOI":"10.1002\/brb3.3072","article-title":"Assessment of clinical outcomes in patients with fibromyalgia: Analysis from the UK Medical Cannabis Registry","volume":"13","author":"Wang","year":"2023","journal-title":"Brain Behav."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1082","DOI":"10.1002\/jts.22550","article-title":"Clinical Manifestations of Trauma Exposure in Fibromyalgia: The Role of Anxiety in the Association Between Posttraumatic Stress Symptoms and Fibromyalgia Status","volume":"33","author":"Miro","year":"2020","journal-title":"J. Trauma. Stress"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s42238-021-00060-6","article-title":"Medical cannabis for the treatment of fibromyalgia syndrome: A retrospective, open-label case series","volume":"3","author":"Mazza","year":"2021","journal-title":"J. Cannabis Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"103160","DOI":"10.1016\/j.msksp.2024.103160","article-title":"Comparative effectiveness of Maitland Spinal Mobilization versus myofascial techniques on pain and symptom severity in women with Fibromyalgia syndrome: A quasi-randomized clinical trial with 3-month follow up","volume":"73","year":"2024","journal-title":"Musculoskelet. Sci. Pract."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1097\/PHM.0000000000002239","article-title":"Effects of Orthopedic Manual Therapy on Pain Sensitization in Patients with Chronic Musculoskeletal Pain: An Umbrella Review With Meta-Meta-analysis","volume":"102","author":"Villafane","year":"2023","journal-title":"Am. J. Phys. Med. Rehabil."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2991","DOI":"10.1523\/JNEUROSCI.4872-05.2006","article-title":"The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum","volume":"26","author":"Kawamura","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1038\/npp.2017.204","article-title":"The Endogenous Cannabinoid System: A Budding Source of Targets for Treating Inflammatory and Neuropathic Pain","volume":"43","author":"Donvito","year":"2018","journal-title":"Neuropsychopharmacology"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.bbi.2023.09.003","article-title":"Anti-satellite glia cell IgG antibodies in fibromyalgia patients are related to symptom severity and to metabolite concentrations in thalamus and rostral anterior cingulate cortex","volume":"114","author":"Fanton","year":"2023","journal-title":"Brain Behav. Immun."}],"container-title":["Life"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/9\/1458\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:47:17Z","timestamp":1760035637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-1729\/15\/9\/1458"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,17]]},"references-count":38,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["life15091458"],"URL":"https:\/\/doi.org\/10.3390\/life15091458","relation":{},"ISSN":["2075-1729"],"issn-type":[{"value":"2075-1729","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,17]]}}}