{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:17:23Z","timestamp":1788175043302,"version":"build-2803163510"},"reference-count":48,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST107-2314-B-038-041-MY3"],"award-info":[{"award-number":["MOST107-2314-B-038-041-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST106-2321-B-001-044"],"award-info":[{"award-number":["MOST106-2321-B-001-044"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST107-2321-B-001-020"],"award-info":[{"award-number":["MOST107-2321-B-001-020"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST108-2321-B-001-005"],"award-info":[{"award-number":["MOST108-2321-B-001-005"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST108-2321-B-001-028-MY2."],"award-info":[{"award-number":["MOST108-2321-B-001-028-MY2."]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"publisher","award":["TMU107-AE1-B24"],"award-info":[{"award-number":["TMU107-AE1-B24"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Cells"],"abstract":"<jats:p>The mechanism of pain chronicity is largely unknown in lumbar radiculopathy (LR). The anatomical location of nerve injury is one of the important factors associated with pain chronicity of LR. Accumulating evidence has shown constriction distal to the dorsal root ganglion (DRG) caused more severe radiculopathy than constriction proximal to the DRG; thereby, the mechanism of pain chronicity in LR could be revealed by comparing the differences in pathological changes of DRGs between nerve constriction distal and proximal to the DRG. Here, we used 2 rat models of LR with nerve constriction distal or proximal to the DRG to probe how the different nerve injury sites could differentially affect pain chronicity and the pathological changes of DRG neuron subpopulations. As expected, rats with nerve constriction distal to the DRG showed more persistent pain behaviors than those with nerve constriction proximal to the DRG in 50% paw withdraw threshold, weight-bearing test, and acetone test. One day after the operation, distal and proximal nerve constriction showed differential pathological changes of DRG. The ratios of activating transcription factor3 (ATF3)-positive DRG neurons were significantly higher in rats with nerve constriction distal to DRG than those with nerve constriction proximal to DRG. In subpopulation analysis, the ratios of ATF3-immunoreactivity (IR) in neurofilament heavy chain (NFH)-positive DRG neurons significantly increased in distal nerve constriction compared to proximal nerve constriction; although, both distal and proximal nerve constriction presented increased ratios of ATF3-IR in calcitonin gene-related peptide (CGRP)-positive DRG neurons. Moreover, the nerve constriction proximal to DRG caused more hypoxia than did that distal to DRG. Together, ATF3 expression in NHF-positive DRG neurons at the acute stage is a potential bio-signature of persistent pain in rat models of LR.<\/jats:p>","DOI":"10.3390\/cells10050992","type":"journal-article","created":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T12:08:30Z","timestamp":1619179710000},"page":"992","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ATF3-Expressing Large-Diameter Sensory Afferents at Acute Stage as Bio-Signatures of Persistent Pain Associated with Lumbar Radiculopathy"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1105-6715","authenticated-orcid":false,"given":"Jiann-Her","family":"Lin","sequence":"first","affiliation":[{"name":"Division of Neurosurgery, Department of Surgery, Taipei Medical University Hospital, Taipei 110301, Taiwan"},{"name":"Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan"},{"name":"Taipei Neuroscience Institute, Taipei Medical University, Taipei 110301, Taiwan"},{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7279-2532","authenticated-orcid":false,"given":"Yu-Wen","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan"},{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5069-9468","authenticated-orcid":false,"given":"Yu-Chia","family":"Chuang","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3642-4115","authenticated-orcid":false,"given":"Cheng-Han","family":"Lee","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4768-5660","authenticated-orcid":false,"given":"Chih-Cheng","family":"Chen","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Academia Sinica, Taipei 115201, Taiwan"},{"name":"Neuroscience Program of Academia Sinica, Academia Sinica, Taipei 115201, Taiwan"},{"name":"Taiwan Mouse Clinic, Biomedical Translation Research Center, Academia Sinica, Taipei 115202, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1097\/BRS.0b013e318183a4a2","article-title":"Sciatica: Review of epidemiological studies and prevalence estimates","volume":"33","author":"Konstantinou","year":"2008","journal-title":"Spine"},{"key":"ref_2","first-page":"119","article-title":"Predicting the outcome of sciatica at short-term follow-up","volume":"52","author":"Vroomen","year":"2002","journal-title":"Br. J. Gen. Pr."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Iversen, T., Solberg, T.K., Wilsgaard, T., Waterloo, K., Brox, J.I., and Ingebrigtsen, T. (2015). Outcome prediction in chronic unilateral lumbar radiculopathy: Prospective cohort study. BMC Musculoskelet Disord, 16.","DOI":"10.1186\/s12891-015-0474-9"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/BF00300292","article-title":"Severe sciatica: A 13-year follow-up of 342 patients","volume":"4","author":"Nykvist","year":"1995","journal-title":"Eur. Spine J."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"10598","DOI":"10.1038\/s41598-017-10641-2","article-title":"Diagnostic accuracy of standardised qualitative sensory test in the detection of lumbar lateral stenosis involving the L5 nerve root","volume":"7","author":"Lin","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1744-8069-8-31","article-title":"Distinct degree of radiculopathy at different levels of peripheral nerve injury","volume":"8","author":"Takiguchi","year":"2012","journal-title":"Mol. Pain"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1007\/s00586-009-1064-z","article-title":"Comparison of neuropathic pain and neuronal apoptosis following nerve root or spinal nerve compression","volume":"18","author":"Sekiguchi","year":"2009","journal-title":"Eur. Spine J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"950","DOI":"10.1097\/01.brs.0000261030.97483.ac","article-title":"Neurophysiologic changes after preganglionic and postganglionic nerve-root constriction: An experimental study in the rat","volume":"32","author":"Matsuda","year":"2007","journal-title":"Spine"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1006\/exnr.1999.7065","article-title":"The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior","volume":"157","author":"Colburn","year":"1999","journal-title":"Exp. Neurol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1097\/00007632-199101000-00012","article-title":"Experimental nerve root compression. A model of acute, graded compression of the porcine cauda equina and an analysis of neural and vascular anatomy","volume":"16","author":"Olmarker","year":"1991","journal-title":"Spine"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1097\/00007632-199009000-00023","article-title":"Blood flow direction in the lumbar nerve root","volume":"15","author":"Naito","year":"1990","journal-title":"Spine"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1744806916681566","DOI":"10.1177\/1744806916681566","article-title":"Distinct calcitonin gene-related peptide expression pattern in primary afferents contribute to different neuropathic symptoms following chronic constriction or crush injuries to the rat sciatic nerve","volume":"12","author":"Zou","year":"2016","journal-title":"Mol. Pain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1016\/S0006-8993(02)03560-6","article-title":"Nerve root injury severity differentially modulates spinal glial activation in a rat lumbar radiculopathy model: Considerations for persistent pain","volume":"956","author":"Winkelstein","year":"2002","journal-title":"Brain Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"617","DOI":"10.2174\/1568026615666150217112652","article-title":"Research Strategies for Pain in Lumbar Radiculopathy Focusing on Acid-Sensing Ion Channels and Their Toxins","volume":"15","author":"Lin","year":"2015","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"162","DOI":"10.5313\/wja.v3.i2.162","article-title":"Lumbar radiculopathy and its neurobiological basis","volume":"3","author":"Lin","year":"2014","journal-title":"World J. Anesth."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1097\/00007632-200002010-00022","article-title":"Spine update. Lumbar foraminal stenosis","volume":"25","author":"Jenis","year":"2000","journal-title":"Spine"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1097\/00007632-199605010-00001","article-title":"Morphometric analysis of the lumbosacral nerve roots and dorsal root ganglia by magnetic resonance imaging","volume":"21","author":"Hasegawa","year":"1996","journal-title":"Spine"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1097\/00007632-199401000-00002","article-title":"Anatomic and radiographic study of dorsal root ganglia","volume":"19","author":"Kikuchi","year":"1994","journal-title":"Spine"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/1744-8069-10-26","article-title":"A simplified up-down method (SUDO) for measuring mechanical nociception in rodents using von Frey filaments","volume":"10","author":"Bonin","year":"2014","journal-title":"Mol. Pain"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1016\/S1063-4584(03)00163-8","article-title":"Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis","volume":"11","author":"Bove","year":"2003","journal-title":"Osteoarthr. Cartil."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/0304-3959(94)90023-X","article-title":"Behavioral signs of ongoing pain and cold allodynia in a rat model of neuropathic pain","volume":"59","author":"Choi","year":"1994","journal-title":"Pain"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1002\/ijc.2910610422","article-title":"Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids","volume":"61","author":"Gross","year":"1995","journal-title":"Int. J. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2185","DOI":"10.1152\/jn.00802.2002","article-title":"Hyperalgesia and neural excitability following injuries to central and peripheral branches of axons and somata of dorsal root ganglion neurons","volume":"89","author":"Song","year":"2003","journal-title":"J. Neurophysiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1016\/j.jpain.2011.04.010","article-title":"Involvement of NGF in the rat model of persistent muscle pain associated with taut band","volume":"12","author":"Hayashi","year":"2011","journal-title":"J. Pain Off. J. Am. Pain Soc."},{"key":"ref_25","first-page":"62","article-title":"The effects of compression on the physiology of nerve roots","volume":"15","author":"Rydevik","year":"1992","journal-title":"J. Manip. Physiol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"577","DOI":"10.1016\/j.neuroscience.2010.07.009","article-title":"The effect of mechanical strain or hypoxia on cell death in subpopulations of rat dorsal root ganglion neurons in vitro","volume":"171","author":"Gladman","year":"2010","journal-title":"Neuroscience"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1097\/00001756-200502080-00002","article-title":"Hypoxia-induced apoptosis in adult rat dorsal root ganglion neurons in vitro","volume":"16","author":"Huang","year":"2005","journal-title":"Neuroreport"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2089","DOI":"10.1097\/00007632-199609150-00006","article-title":"The effects of mechanical compression and hypoxia on nerve root and dorsal root ganglia. An analysis of ectopic firing using an in vitro model","volume":"21","author":"Sugawara","year":"1996","journal-title":"Spine"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Xie, R.G., Chu, W.G., Hu, S.J., and Luo, C. (2018). Characterization of Different Types of Excitability in Large Somatosensory Neurons and Its Plastic Changes in Pathological Pain States. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010161"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1006\/mcne.1999.0814","article-title":"Activating transcription factor 3 (ATF3) induction by axotomy in sensory and motoneurons: A novel neuronal marker of nerve injury","volume":"15","author":"Tsujino","year":"2000","journal-title":"Mol. Cell Neurosci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1213\/01.ANE.0000227067.35946.A2","article-title":"Perioperative analgesia to prevent chronic postmastectomy pain","volume":"103","author":"Kehlet","year":"2006","journal-title":"Anesth. Analg."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.expneurol.2016.06.002","article-title":"Cutaneous tissue damage induces long-lasting nociceptive sensitization and regulation of cellular stress- and nerve injury-associated genes in sensory neurons","volume":"283","author":"Rau","year":"2016","journal-title":"Exp. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Ogawa, N., Kawai, H., Terashima, T., Kojima, H., Oka, K., Chan, L., and Maegawa, H. (2014). Gene therapy for neuropathic pain by silencing of TNF-alpha expression with lentiviral vectors targeting the dorsal root ganglion in mice. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092073"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/S0304-3959(02)00296-8","article-title":"Contribution of injured and uninjured dorsal root ganglion neurons to pain behavior and the changes in gene expression following chronic constriction injury of the sciatic nerve in rats","volume":"101","author":"Obata","year":"2003","journal-title":"Pain"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.brainres.2007.10.044","article-title":"Calcitonin gene-related peptide dynamics in rat dorsal root ganglia and spinal cord following different sciatic nerve injuries","volume":"1187","author":"Zheng","year":"2008","journal-title":"Brain Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1111\/j.1460-9568.1991.tb00820.x","article-title":"Differential Regulation of Calcitonin Gene-related Peptide (CGRP) in Regenerating Rat Facial Nucleus and Dorsal Root Ganglion","volume":"3","author":"Dumoulin","year":"1991","journal-title":"Eur. J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/BF02284798","article-title":"Sciatic nerve injury in the adult rat: Comparison of effects on oligosaccharide, CGRP and GAP43 immunoreactivity in primary afferents following two types of trauma","volume":"25","author":"Groves","year":"1996","journal-title":"J. Neurocytol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/S0014-2999(03)01753-9","article-title":"Pharmacological sensitivity and gene expression analysis of the tibial nerve injury model of neuropathic pain","volume":"470","author":"Hofmann","year":"2003","journal-title":"Eur. J. Pharm."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/cne.20209","article-title":"Effects of spinal nerve ligation on immunohistochemically identified neurons in the L4 and L5 dorsal root ganglia of the rat","volume":"475","author":"Hammond","year":"2004","journal-title":"J. Comp. Neurol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1016\/S0304-3959(98)00111-0","article-title":"Change in mRNAs for neuropeptides and the GABA(A) receptor in dorsal root ganglion neurons in a rat experimental neuropathic pain model","volume":"78","author":"Fukuoka","year":"1998","journal-title":"Pain"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1016\/S0306-4522(97)00258-3","article-title":"Calcitonin gene-related peptide increase in the rat spinal dorsal horn and dorsal column nucleus following peripheral nerve injury: Up-regulation in a subpopulation of primary afferent sensory neurons","volume":"82","author":"Miki","year":"1998","journal-title":"Neuroscience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"8370","DOI":"10.1523\/JNEUROSCI.23-23-08370.2003","article-title":"Enhanced evoked excitatory transmitter release in experimental neuropathy requires descending facilitation","volume":"23","author":"Gardell","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_43","unstructured":"NASS Evidence-Based Clinical Guidelines Committee (2012). Evidence-Based Clnical Guidlines for Multidisciplinary Spine Care: Diagnosis and Treatment of Lumbar Disc Herniation with Lumbar Radiculopathy, North American Spine Society."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.expneurol.2006.11.016","article-title":"p38 activation in uninjured primary afferent neurons and in spinal microglia contributes to the development of neuropathic pain induced by selective motor fiber injury","volume":"204","author":"Xu","year":"2007","journal-title":"Exp. Neurol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.expneurol.2012.12.007","article-title":"The up-regulation of IL-6 in DRG and spinal dorsal horn contributes to neuropathic pain following L5 ventral root transection","volume":"241","author":"Wei","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.pain.2010.06.005","article-title":"TNF-alpha contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury","volume":"151","author":"He","year":"2010","journal-title":"Pain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.bbi.2014.08.003","article-title":"Calpain-2 contributes to neuropathic pain following motor nerve injury via up-regulating interleukin-6 in DRG neurons","volume":"44","author":"Zang","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"RC140","DOI":"10.1523\/JNEUROSCI.21-08-j0002.2001","article-title":"Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers","volume":"21","author":"Wu","year":"2001","journal-title":"J. Neurosci."}],"updated-by":[{"DOI":"10.3390\/cells13242061","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2021,4,23]],"date-time":"2021-04-23T00:00:00Z","timestamp":1619136000000}}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/992\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:42:32Z","timestamp":1754260952000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/5\/992"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,23]]},"references-count":48,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["cells10050992"],"URL":"https:\/\/doi.org\/10.3390\/cells10050992","relation":{"correction":[{"id-type":"doi","id":"10.3390\/cells13242061","asserted-by":"object"}]},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,23]]}}}