{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T12:30:10Z","timestamp":1785933010854,"version":"3.56.0"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T00:00:00Z","timestamp":1671494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82171213"],"award-info":[{"award-number":["82171213"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013795","name":"Fujian Medical University","doi-asserted-by":"publisher","award":["2021QH2005"],"award-info":[{"award-number":["2021QH2005"]}],"id":[{"id":"10.13039\/501100013795","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Mol. Neurosci."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The aim of this study was to investigate the effect and possible mechanisms of the blood-nerve barrier (BNB) and the coagulation-anticoagulation system in modulating the mechanical allodynia in a trigeminal neuralgia (TN) rat model induced by chronic compression of the trigeminal root entry zone (TREZ).<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Von Frey filaments were applied to determine the orofacial mechanical allodynia threshold. The BNB permeability was evaluated by Evans blue extravasation test. Immunohistochemical staining and laser confocal microscopy were used to measure the length of the depletion zones of the nodes of Ranvier in the TREZ, the diameter of nerve fibers and the length of the nodal gap. The transcriptional levels of prothrombin and endogenous thrombin inhibitor protease nexin-1 (PN-1) in the TREZ of TN rats were assessed by RT-qPCR. A Western blotting assay was performed to detect the expression of paranodal proteins neurofascin-155 (NF155) and neurofascin-125 (NF125) in the TREZ. The spatiotemporal expression pattern of thrombin activated receptor (i.e. protease activated receptor 1, PAR1) in TREZ were defined by immunostaining and immunoblotting assays. PAR1 receptor inhibitors SCH79797 were administrated to TN rats to analyze the effect of thrombin-PAR1 on orofacial hyperalgesia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A compression injury of a rat\u2019s TREZ successfully induced TN-like behavior and was accompanied by the destruction of the permeability of the BNB and the promotion of prothrombin and thrombin inhibitor protease nexin-1 (PN-1) expression. The expression of the paranodal proteins neurofascin-155 (NF155) and neurofascin-125 (NF125) was increased, while the nodal gap length of the nodes of Ranvier was widened and the length of node-depleted zones was shortened. Moreover, the expression of PAR1 within the TREZ was upregulated at an early stage of TN, and administration of the PAR1 antagonist SCH79797 effectively ameliorated orofacial mechanical allodynia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>A compression injury of the TREZ increased the permeability of the BNB and induced disturbances in the local coagulation-anticoagulation system, concomitant with the structural changes in the nodes of Ranvier, thrombin-PAR1 may play a critical role in modulating orofacial mechanical hyperalgesia in a TN rat model.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fnmol.2022.1059980","type":"journal-article","created":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T14:33:57Z","timestamp":1671546837000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":6,"title":["Blood-nerve barrier disruption and coagulation system activation induced by mechanical compression injury participate in the peripheral sensitization of trigeminal neuralgia"],"prefix":"10.3389","volume":"15","author":[{"given":"Lu-Xi","family":"Zhou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shao-Wei","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rong-Hui","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Lin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue-Feng","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dao-Shu","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-Qing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,12,20]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1007\/7651_2020_316","article-title":"Evaluation of blood-brain barrier integrity using vascular permeability markers: Evans blue, sodium fluorescein, albumin-alexa fluor conjugates, and horseradish peroxidase","volume":"2367","author":"Ahishali","year":"2021","journal-title":"Methods Mol. Biol."},{"key":"ref2","doi-asserted-by":"publisher","first-page":"e23329","DOI":"10.7554\/eLife.23329","article-title":"Node of Ranvier length as a potential regulator of myelinated axon conduction speed","volume":"6","author":"Arancibia-Carcamo","year":"2017","journal-title":"elife"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1002\/jnr.20270","article-title":"Increased thrombin inhibition in experimental autoimmune encephalomyelitis","volume":"79","author":"Beilin","year":"2005","journal-title":"J. Neurosci. Res."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1950","DOI":"10.3390\/biomedicines9121950","article-title":"Complement and coagulation system crosstalk in synaptic and neural conduction in the central and peripheral nervous systems","volume":"9","author":"Berkowitz","year":"2021","journal-title":"Biomedicine"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"876","DOI":"10.1055\/s-0033-1357482","article-title":"Coagulation in inflammatory diseases of the central nervous system","volume":"39","author":"Chapman","year":"2013","journal-title":"Semin. Thromb. Hemost."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"E191","DOI":"10.1073\/pnas.1619553114","article-title":"Ultrastructural anatomy of nodes of Ranvier in the peripheral nervous system as revealed by STED microscopy","volume":"114","author":"D'Este","year":"2017","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/0896-6273(91)90060-d","article-title":"Prothrombin mRNA is expressed by cells of the nervous system","volume":"6","author":"Dihanich","year":"1991","journal-title":"Neuron"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1089\/neu.2012.2600","article-title":"Ketorolac reduces spinal astrocytic activation and PAR1 expression associated with attenuation of pain after facet joint injury","volume":"30","author":"Dong","year":"2013","journal-title":"J. Neurotrauma"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"11832","DOI":"10.1073\/pnas.1811013115","article-title":"Regulation of myelin structure and conduction velocity by perinodal astrocytes","volume":"115","author":"Dutta","year":"2018","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"183211","DOI":"10.1016\/j.bbamem.2020.183211","article-title":"Molecular organization and function of vertebrate septate-like junctions","volume":"1862","author":"Faivre-Sarrailh","year":"2020","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"1145","DOI":"10.1160\/TH09-12-0848","article-title":"The role of thrombin and protease-activated receptors in pain mechanisms","volume":"103","author":"Garcia","year":"2010","journal-title":"Thromb. Haemost."},{"key":"ref12","doi-asserted-by":"publisher","first-page":"2043","DOI":"10.4103\/1673-5374.262568","article-title":"The neuro-glial coagulonome: the thrombin receptor and coagulation pathways as major players in neurological diseases","volume":"14","author":"Gofrit","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12974-015-0469-3","article-title":"Modeling leukocyte trafficking at the human blood-nerve barrier in vitro and in vivo geared towards targeted molecular therapies for peripheral neuroinflammation","volume":"13","author":"Greathouse","year":"2016","journal-title":"J. Neuroinflammation"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"18966","DOI":"10.1016\/S0021-9258(17)46721-4","article-title":"Protease nexin-1, a thrombin inhibitor, is regulated by interleukin-1 and dexamethasone in normal human fibroblasts","volume":"268","author":"Guttridge","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1002\/glia.20129","article-title":"Caspr reveals an aggregation of nodes and flanking node free zones at the rat trigeminal sensory root and dorsal root entry zones","volume":"49","author":"Henry","year":"2005","journal-title":"Glia"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1016\/s0014-4827(02)00035-6","article-title":"Loss and recovery of the blood-nerve barrier in the rat sciatic nerve after crush injury are associated with expression of intercellular junctional proteins","volume":"284","author":"Hirakawa","year":"2003","journal-title":"Exp. Cell Res."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1177\/1073858418783959","article-title":"Microglia-astrocyte crosstalk: an intimate molecular conversation","volume":"25","author":"Jha","year":"2019","journal-title":"Neuroscientist"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"74","DOI":"10.1007\/s11916-019-0810-0","article-title":"A comprehensive review of trigeminal neuralgia","volume":"23","author":"Jones","year":"2019","journal-title":"Curr. Pain Headache Rep."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"84","DOI":"10.3390\/ijms17010084","article-title":"The importance of thrombin in cerebral injury and disease","volume":"17","author":"Krenzlin","year":"2016","journal-title":"Int. J. Mol. Sci."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"9494352","DOI":"10.1155\/2020\/9494352","article-title":"Reactive astrogliosis: implications in spinal cord injury progression and therapy","volume":"2020","author":"Li","year":"2020","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1016\/j.pain.2014.01.026","article-title":"Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief","volume":"155","author":"Lim","year":"2014","journal-title":"Pain"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"828","DOI":"10.3171\/2018.5.JNS172948","article-title":"Immunohistochemical analysis of histone H3 acetylation in the trigeminal root entry zone in an animal model of trigeminal neuralgia","volume":"131","author":"Lin","year":"2018","journal-title":"J. Neurosurg."},{"key":"ref23","doi-asserted-by":"publisher","first-page":"e52378","DOI":"10.7554\/eLife.52378","article-title":"Nodal beta spectrins are required to maintain Na(+) channel clustering and axon integrity","volume":"9","author":"Liu","year":"2020","journal-title":"elife"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"1893","DOI":"10.1007\/s11064-019-02824-2","article-title":"Glial plasticity in the trigeminal root entry zone of a rat trigeminal neuralgia animal model","volume":"44","author":"Luo","year":"2019","journal-title":"Neurochem. Res."},{"key":"ref25","doi-asserted-by":"publisher","first-page":"3014","DOI":"10.1002\/ar.24364","article-title":"Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expressions in the trigeminal root entry zone and trigeminal ganglion neurons of a trigeminal neuralgia rat model","volume":"303","author":"Luo","year":"2020","journal-title":"Anat. Rec."},{"key":"ref26","doi-asserted-by":"publisher","first-page":"187","DOI":"10.36076\/ppj.2012\/15\/187","article-title":"An animal model for trigeminal neuralgia by compression of the trigeminal nerve root","volume":"15","author":"Luo","year":"2012","journal-title":"Pain Physician"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1097\/j.pain.0000000000000444","article-title":"Early alterations of hedgehog signaling pathway in vascular endothelial cells after peripheral nerve injury elicit blood-nerve barrier disruption, nerve inflammation, and neuropathic pain development","volume":"157","author":"Moreau","year":"2016","journal-title":"Pain"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"136","DOI":"10.3389\/fncel.2017.00136","article-title":"Axonal membranes and their domains: assembly and function of the axon initial segment and node of ranvier","volume":"11","author":"Nelson","year":"2017","journal-title":"Front. Cell. 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Spine"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1160\/TH08-03-0131","article-title":"Prothrombin\/thrombin and the thrombin receptors PAR-1 and PAR-4 in the brain: localization, expression and participation in neurodegenerative diseases","volume":"100","author":"Sokolova","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref38","doi-asserted-by":"publisher","first-page":"209","DOI":"10.1042\/AN20130025","article-title":"Node of Ranvier disruption as a cause of neurological diseases","volume":"5","author":"Susuki","year":"2013","journal-title":"ASN Neuro."},{"key":"ref39","doi-asserted-by":"publisher","first-page":"167","DOI":"10.3390\/brainsci9070167","article-title":"Sex differences in the effect of alcohol drinking on myelinated axons in the anterior cingulate cortex of adolescent rats","volume":"9","author":"Tavares","year":"2019","journal-title":"Brain Sci."},{"key":"ref40","doi-asserted-by":"publisher","first-page":"113272","DOI":"10.1016\/j.expneurol.2020.113272","article-title":"Biology of the human blood-nerve barrier in health and disease","volume":"328","author":"Ubogu","year":"2020","journal-title":"Exp. Neurol."},{"key":"ref41","doi-asserted-by":"publisher","first-page":"776","DOI":"10.1523\/JNEUROSCI.3105-14.2015","article-title":"PAR1-activated astrocytes in the nucleus of the solitary tract stimulate adjacent neurons via NMDA receptors","volume":"35","author":"Vance","year":"2015","journal-title":"J. Neurosci."},{"key":"ref42","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/1744-8069-6-61","article-title":"Protease activated receptors 1 and 4 sensitize TRPV1 in nociceptive neurones","volume":"6","author":"Vellani","year":"2010","journal-title":"Mol. Pain"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/978-1-60761-938-3_6","article-title":"The blood-nerve barrier: structure and functional significance","volume":"686","author":"Weerasuriya","year":"2011","journal-title":"Methods Mol. 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