{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T05:49:35Z","timestamp":1787636975963,"version":"build-2736575974"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T00:00:00Z","timestamp":1777852800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurosci."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>This study investigated whether manual therapy applied to tendon organs ameliorated neuromuscular dysfunction in rats with spasticity induced by upper motor neuron injury associated with spastic cerebral palsy, and analyzed the potential involvement of the C-fiber-mediated CaMKII signaling pathway.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male rats were used to establish palsy models and divided into groups: Control, Model, Manual Therapy (MT), Capsaicin Treatment, Sham, CaMKII Inhibitor, and DMSO Solvent groups. Except for Control, all underwent pyramidal-tract destruction. After modeling, the MT group received manual therapy on the left-lower leg tendon organs. The Capsaicin group underwent sciatic nerve capsaicin treatment for C-fiber block on days 2 and 7; the Sham group had sciatic nerve exposure only. Both received daily manual therapy intervention for 14\u202fdays. The CaMKII Inhibitor and DMSO Solvent groups received intrathecal injections every 2\u202fdays (7 times total) without manual intervention. Spasticity-related behavioral indices, molecular expression, and neurotransmitter levels were assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Manual therapy reduced the neurological deficit scores and muscle spasticity scores of model rats, improved the pathological morphology of the pyramidal tract and skeletal muscle, and regulated the expression of key molecules and neurotransmitters in the spinal cord and hippocampus. The therapeutic effects of manual therapy were significantly attenuated after C-fiber blockage, and although CaMKII inhibition could partially mimic the neuromodulatory effects of manual therapy, its efficacy in alleviating spasticity was inferior to that of manual-therapy intervention.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Manual therapy appears to regulate CaMKII signaling via C-fiber afferent pathways to ameliorate neuromuscular dysfunction in a rat model of spasticity induced by pyramidal-tract lesion, thereby providing experimental evidence for the clinical application of optimized manual therapy parameters in the management of spasticity in patients with cerebral palsy.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fnins.2026.1780013","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T05:34:29Z","timestamp":1777872869000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Manual therapy ameliorates neuromuscular dysfunction in spastic model rat: involvement of the C-Fiber-mediated CaMKII pathway"],"prefix":"10.3389","volume":"20","author":[{"given":"Yitian","family":"Lai","sequence":"first","affiliation":[{"name":"The Second Hospital of Hunan University of Chinese Medicine","place":["Changsha, China"]},{"name":"College of Acupuncture-Moxibustion-Tuina and Rehabilitation, Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanbo","family":"Fan","sequence":"additional","affiliation":[{"name":"College of Acupuncture-Moxibustion-Tuina and Rehabilitation, Hunan University of Chinese Medicine","place":["Changsha, China"]},{"name":"Integrated Traditional Chinese and Western Medicine Hospital Affiliated with Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Zeng","sequence":"additional","affiliation":[{"name":"College of Acupuncture-Moxibustion-Tuina and Rehabilitation, Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Acupuncture-Moxibustion-Tuina and Rehabilitation, Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wu","family":"Li","sequence":"additional","affiliation":[{"name":"The Second Hospital of Hunan University of Chinese Medicine","place":["Changsha, China"]},{"name":"College of Acupuncture-Moxibustion-Tuina and Rehabilitation, Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangshan","family":"Li","sequence":"additional","affiliation":[{"name":"The Second Hospital of Hunan University of Chinese Medicine","place":["Changsha, China"]},{"name":"College of Acupuncture-Moxibustion-Tuina and Rehabilitation, Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Chen","sequence":"additional","affiliation":[{"name":"The Second Hospital of Hunan University of Chinese Medicine","place":["Changsha, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"3296","DOI":"10.1007\/s11064-023-03983-z","article-title":"Capsaicin, the vanilloid receptor TRPV1 agonist in neuroprotection: mechanisms involved and significance","volume":"48","author":"Abdel-Salam","year":"2023","journal-title":"Neurochem. Res."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"150218","DOI":"10.1016\/j.bbrc.2024.150218","article-title":"GABAergic implications in anxiety and related disorders","volume":"724","author":"Arora","year":"2024","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"102802","DOI":"10.1016\/j.pneurobio.2025.102802","article-title":"CMTR1-catalyzed 2\u2032-O-methylation promotes NMDA receptor signaling, long-term potentiation and memory","volume":"251","author":"Azeem","year":"2025","journal-title":"Prog. Neurobiol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1038\/sc.2015.230","article-title":"Modified Ashworth Scale and spasm frequency score in spinal cord injury: reliability and correlation","volume":"54","author":"Baunsgaard","year":"2016","journal-title":"Spinal Cord"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1038\/nrn.2016.68","article-title":"Synaptic plasticity in the anterior cingulate cortex in acute and chronic pain","volume":"17","author":"Bliss","year":"2016","journal-title":"Nat. Rev. Neurosci."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1111\/dmcn.14252","article-title":"International expert recommendations of clinical features to prompt referral for diagnostic assessment of cerebral palsy","volume":"62","author":"Boychuck","year":"2020","journal-title":"Dev. Med. Child Neurol."},{"key":"ref7","volume-title":"Effect of Pressing Manipulation on Muscle tone and Changes of Inhibitory Neurotransmitters in the Anterior Horn of the Spinal Cord in Rats with Post-Stroke Muscle Spasticity","author":"Chen","year":"2015"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1007\/s11726-020-1161-4","article-title":"Effect of an-pressing manipulation on post-stroke muscle spasticity in rats and its mechanism study","volume":"18","author":"Chu","year":"2020","journal-title":"J. Acupunct. Tuina Sci."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"1588084","DOI":"10.3389\/fphys.2025.1588084","article-title":"Biomechanical and clinical differences in muscle tone, stiffness, range of motion, and pain perception in children with cerebral palsy: a cross-sectional study","volume":"16","author":"Gonz\u00e1lez-Matilla","year":"2025","journal-title":"Front. Physiol."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1001\/jamaoncol.2019.5233","article-title":"Clinical evidence for association of acupuncture and acupressure with improved cancer pain: a systematic review and meta-analysis","volume":"6","author":"He","year":"2020","journal-title":"JAMA Oncol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1016\/j.neuron.2013.12.024","article-title":"CaMKII: claiming center stage in postsynaptic function and organization","volume":"81","author":"Hell","year":"2014","journal-title":"Neuron"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/s12987-024-00534-8","article-title":"Alterations in brain fluid physiology during the early stages of development of ischaemic oedema","volume":"21","author":"Hladky","year":"2024","journal-title":"Fluids Barriers CNS."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"777","DOI":"10.1038\/s41593-021-00843-3","article-title":"CaMKII activation persistently segregates postsynaptic proteins via liquid phase separation","volume":"24","author":"Hosokawa","year":"2021","journal-title":"Nat. Neurosci."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"4360","DOI":"10.12307\/2024.552","article-title":"Effect of tuina pressing manipulation with different intensities on myofascial trigger points in rats","volume":"28","author":"Jiang","year":"2024","journal-title":"Chin. J. Tissue Eng. Res."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"335","DOI":"10.3969\/j-issn-1006-9852-2021-05-005","article-title":"Study on the effect of pressing on soft tissue tension of myofascial trigger points in rats and its mechanism of action","volume":"27","author":"Jiang","year":"2021","journal-title":"Chin. J. Pain Med."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1593","DOI":"10.3969\/j.issn.1001-1242.2022.12.001","article-title":"Effect of pressing on mitochondrial autophagy level and PINK1\/Parkin pathway in rats with chronic myofascial trigger points","volume":"37","author":"Jiang","year":"2022","journal-title":"Chin. J. Rehabil. 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Neurosci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.cmet.2016.09.017","article-title":"Mammalian mitochondria and aging: an update","volume":"25","author":"Kauppila","year":"2017","journal-title":"Cell Metab."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1016\/j.neuropharm.2006.09.008","article-title":"Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system","volume":"52","author":"Klein","year":"2007","journal-title":"Neuropharmacology"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1619","DOI":"10.1016\/s0140-6736(04)16207-7","article-title":"Cerebral palsy","volume":"363","author":"Koman","year":"2004","journal-title":"Lancet"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3389\/fncel.2015.00058","article-title":"Epigenetic mechanisms in neurological and neurodegenerative diseases","volume":"9","author":"Landgrave-G\u00f3mez","year":"2015","journal-title":"Front. 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USA"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"7272","DOI":"10.3390\/ijms21197272","article-title":"CaMKII\u03b2 in neuronal development and plasticity: an emerging candidate in brain diseases","volume":"21","author":"Nicole","year":"2020","journal-title":"Int. J. Mol. Sci."},{"key":"ref28","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1111\/dmcn.14024","article-title":"Selective motor control and gross motor function in bilateral spastic cerebral palsy","volume":"61","author":"Noble","year":"2019","journal-title":"Dev. Med. Child Neurol."},{"key":"ref29","doi-asserted-by":"publisher","first-page":"3012","DOI":"10.1096\/fj.11-191999","article-title":"Hypoxia and exercise provoke both lactate release and lactate oxidation by the human brain","volume":"26","author":"Overgaard","year":"2012","journal-title":"FASEB J."},{"key":"ref30","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1016\/0166-2236(90)90084-N","article-title":"Presynaptic inhibition of muscle spindle and tendon organ afferents in the mammalian spinal cord","volume":"13","author":"Rudomin","year":"1990","journal-title":"Trends Neurosci."},{"key":"ref31","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1007\/s00381-007-0379-5","article-title":"Selective dorsal rhizotomy for spastic cerebral palsy: a review","volume":"23","author":"Steinbok","year":"2007","journal-title":"Childs Nerv. Syst."},{"key":"ref32","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1007\/s12017-021-08675-x","article-title":"Tranilast, a transient receptor potential vanilloid 2 channel (TRPV2) inhibitor attenuates amyloid \u03b2-induced cognitive impairment: possible mechanisms","volume":"24","author":"Thapak","year":"2022","journal-title":"NeuroMolecular Med."},{"key":"ref33","doi-asserted-by":"publisher","first-page":"4395","DOI":"10.1038\/s41467-020-18074-8","article-title":"Interneuron-specific plasticity at parvalbumin and somatostatin inhibitory synapses onto CA1 pyramidal neurons shapes hippocampal output","volume":"11","author":"Udakis","year":"2020","journal-title":"Nat. Commun."},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1139","DOI":"10.1152\/japplphysiol.00965.2024","article-title":"Revisiting hyper-resistance to muscle stretch in cerebral palsy: muscle hypo-extensibility is more of an issue than hyperreflexia","volume":"139","author":"Valad\u00e3o","year":"2025","journal-title":"J. Appl. Physiol. (1985)"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1782","DOI":"10.1152\/japplphysiol.00641.2019","article-title":"Age-related responses to a bout of mechanotherapy in skeletal muscle of rats","volume":"127","author":"Van Pelt Dw","year":"2019","journal-title":"J. Appl. Physiol. (1985)"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"851","DOI":"10.1523\/JNEUROSCI.3292-05.2006","article-title":"Calcium calmodulin-stimulated adenylyl cyclases contribute to activation of extracellular signal-regulated kinase in spinal dorsal horn neurons in adult rats and mice","volume":"26","author":"Wei","year":"2006","journal-title":"J. Neurosci."},{"key":"ref37","doi-asserted-by":"publisher","first-page":"934","DOI":"10.1002\/jnr.21013","article-title":"Role of phosphorylation of ERK in induction and maintenance of LTP of the C-fiber evoked field potentials in spinal dorsal horn","volume":"84","author":"Xin","year":"2006","journal-title":"J. Neurosci. Res."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"3255","DOI":"10.3969\/j.issn.1673-5374.2013.34.010","article-title":"Establishing a rat model of spastic cerebral palsy by targeted ethanol injection","volume":"8","author":"Yu","year":"2013","journal-title":"Neural Regen. Res."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1154","DOI":"10.1161\/CIRCULATIONAHA.121.055920","article-title":"Novel CaMKII-\u03b4 inhibitor Hesperadin exerts dual functions to ameliorate cardiac ischemia\/reperfusion injury and inhibit tumor growth","volume":"145","author":"Zhang","year":"2022","journal-title":"Circulation"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"228","DOI":"10.1016\/j.brainres.2004.03.034","article-title":"A C-fiber reflex inhibition induced by electroacupuncture with different intensities applied at homotopic and heterotopic acupoints in rats selectively destructive effects on myelinated and unmyelinated afferent fibers","volume":"1011","author":"Zhu","year":"2004","journal-title":"Brain Res."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"e1995242025","DOI":"10.1523\/JNEUROSCI.1995-24.2025","article-title":"CaMKII\u03b2-mediated phosphorylation enhances protein stability of Spastin to promote neurite outgrowth","volume":"45","author":"Zou","year":"2025","journal-title":"J. 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