{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:16:55Z","timestamp":1788239815474,"version":"build-2803163510"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100005191","name":"Craig H. Neilsen Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100005191","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Prior research has shown that regional application of an anesthetic (lidocaine) via a lumbar puncture can attenuate pain-induced secondary tissue loss after spinal cord injury (SCI). Applying lidocaine rostral to injury (at T2) also had a protective effect, suggesting neural signaling to\/from rostral systems contributes to pain-induced tissue loss after SCI. The present study examined whether regional anesthesia protects the injured spinal cord when applied immediately after injury in the absence of additional pain. We hypothesized that inhibiting cellular activity in the region of injury would have a protective effect and that increasing the duration of treatment (from 1.5 to 12\u202fh) would amplify this outcome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Male rats received a severe T12 contusion injury and were fitted with a catheter with the tip positioned either at L4 (Experiment 1) or at T2 (Experiment 2). Infusion of a marker at L4 showed dispersion extending to the site of injury. Infusion at T2 was restricted to the upper thoracic region. Regional anesthesia was induced using bupivacaine due to its wide use and long duration of action. Immediately after injury, animals received 30\u202f\u03bcL of 0.75% bupivacaine or saline through the implanted catheter. Separate groups then received 0, 1, 3, or 7 additional infusions at 90\u202fmin intervals, yielding four treatment conditions: 1.5, 3, 6, or 12\u202fh of local anesthesia. A day after injury, locomotor performance was assessed and a 1\u202fcm region of injured spinal cord was taken to be assayed for markers of hemorrhage, programmed cell death, and inflammation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Animals that received bupivacaine rostral to injury for 3\u201312\u202fh exhibited improved locomotor recovery, less hemorrhage, and reduced cell death at the site of injury. Treatment at L4 was less effective in attenuating hemorrhage and cell death. In both experiments, there was no indication that increasing the duration of treatment beyond 3\u202fh had added benefit.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>The results suggest that local application of an anesthetic at, or rostral to, a SCI may have a protective effect.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1880792","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:26:46Z","timestamp":1788236806000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Regional anesthesia after spinal cord injury attenuates behavioral loss, hemorrhage, and cell death"],"prefix":"10.3389","volume":"17","author":[{"given":"Natsuka","family":"Kobayashi","sequence":"first","affiliation":[{"name":"Behavioral and Cellular Neuroscience, Department of Psychological & Brain Sciences","place":["College Station, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob A.","family":"Davis","sequence":"additional","affiliation":[{"name":"Weill Institute for Neurosciences, Department of Neurological Surgery, University of California, San Francisco","place":["San Francisco, CA, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Calvin T.","family":"Phinney","sequence":"additional","affiliation":[{"name":"Behavioral and Cellular Neuroscience, Department of Psychological & Brain Sciences","place":["College Station, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James W.","family":"Grau","sequence":"additional","affiliation":[{"name":"Behavioral and Cellular Neuroscience, Department of Psychological & Brain Sciences","place":["College Station, TX, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"17018","DOI":"10.1038\/nrdp.2017.18","article-title":"Traumatic spinal cord injury","volume":"3","author":"Ahuja","year":"2017","journal-title":"Nat Rev Dis Primers"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1089\/neu.2004.21.1795","article-title":"Uncontrollable stimulation undermines recovery after spinal cord injury","volume":"21","author":"Grau","year":"2004","journal-title":"J Neurotrauma"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1873","DOI":"10.1089\/neu.2016.4626","article-title":"When pain hurts: nociceptive stimulation induces a state of maladaptive plasticity and impairs recovery after spinal cord injury","volume":"34","author":"Grau","year":"2017","journal-title":"J Neurotrauma"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1016\/j.expneurol.2018.09.018","article-title":"Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury","volume":"311","author":"Turtle","year":"2019","journal-title":"Exp Neurol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"112695","DOI":"10.1016\/j.physbeh.2019.112695","article-title":"A brief period of moderate noxious stimulation induces hemorrhage and impairs locomotor recovery after spinal cord injury","volume":"212","author":"Strain","year":"2019","journal-title":"Physiol Behav"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"27","DOI":"10.3389\/fnsys.2018.00027","article-title":"Pain input after spinal cord injury (SCI) undermines long-term recovery and engages signal pathways that promote cell death","volume":"12","author":"Turtle","year":"2018","journal-title":"Front Syst Neurosci"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"632","DOI":"10.1089\/neu.2016.4507","article-title":"Neurobiological effects of morphine after spinal cord injury","volume":"34","author":"Hook","year":"2017","journal-title":"J Neurotrauma"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1186\/s12868-022-00739-3","article-title":"Morphine-induced changes in the function of microglia and macrophages after acute spinal cord injury","volume":"23","author":"Terminel","year":"2022","journal-title":"BMC Neurosci"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"281","DOI":"10.1016\/j.bbr.2007.02.035","article-title":"The impact of morphine after a spinal cord injury","volume":"179","author":"Hook","year":"2007","journal-title":"Behav Brain Res"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"1200","DOI":"10.1089\/neu.2016.4778","article-title":"Pain input impairs recovery after spinal cord injury: treatment with lidocaine","volume":"34","author":"Turtle","year":"2017","journal-title":"J Neurotrauma"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"44","DOI":"10.3389\/fnsys.2019.00044","article-title":"Brain-dependent processes fuel pain-induced Hemorrhage after spinal cord injury","volume":"13","author":"Reynolds","year":"2019","journal-title":"Front Syst Neurosci"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1729","DOI":"10.1089\/neu.2019.6973","article-title":"Pharmacological transection of brain-spinal cord communication blocks pain-induced Hemorrhage and locomotor deficits after spinal cord injury in rats","volume":"37","author":"Davis","year":"2020","journal-title":"J Neurotrauma"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"2552","DOI":"10.1089\/neu.2022.0449","article-title":"General Anesthesia blocks pain-induced Hemorrhage and locomotor deficits after spinal cord injury in rats","volume":"40","author":"Davis","year":"2023","journal-title":"J Neurotrauma"},{"key":"ref14","volume-title":"Physiology, Nociceptive Pathways","author":"Kendroud","year":"2025"},{"key":"ref15","volume-title":"Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e","author":"Catterall","year":"2017"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1213\/00000539-199907000-00021","article-title":"Prolongation of nerve and epidural anesthetic blockade by bupivacaine in a lipid emulsion","volume":"89","author":"Lazaro","year":"1999","journal-title":"Anesth Analg"},{"key":"ref17","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/neu.1995.12.1","article-title":"A sensitive and reliable locomotor rating scale for open field testing in rats","volume":"12","author":"Basso","year":"1995","journal-title":"J Neurotrauma"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1601","DOI":"10.1089\/neu.1995.12.1","article-title":"A simple post hoc transformation that improves the metric properties of the BBB scale for rats with moderate to severe spinal cord injury","volume":"21","author":"Ferguson","year":"2004","journal-title":"J Neurotrauma"},{"key":"ref19","volume-title":"Optical Absorption of Hemoglobin","author":"Prahl","year":"1999"},{"key":"ref20","article-title":"Pentobarbital anesthesia after spinal cord injury (SCI) blocks hemorrhage induced by stress","author":"Davis","year":"2022"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1038\/sj.cdd.4400476","article-title":"Emerging roles of caspase-3 in apoptosis","volume":"6","author":"Porter","year":"1999","journal-title":"Cell Death Differ"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"5132","DOI":"10.3390\/ijms22105132","article-title":"When the blood hits your brain: the neurotoxicity of extravasated blood","volume":"22","author":"Stokum","year":"2021","journal-title":"Int J Mol Sci"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"1128","DOI":"10.1046\/j.1471-4159.2001.00313.x","article-title":"Oxyhemoglobin induces caspase-mediated cell death in cerebral endothelial cells","volume":"77","author":"Meguro","year":"2001","journal-title":"J Neurochem"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1016\/j.brainres.2008.05.013","article-title":"Nociceptive inhibition prevents inflammatory pain induced changes in the blood-brain barrier","volume":"1221","author":"Campos","year":"2008","journal-title":"Brain Res"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1186\/s12974-021-02337-2","article-title":"Inflammation after spinal cord injury: a review of the critical timeline of signaling cues and cellular infiltration","volume":"18","author":"Hellenbrand","year":"2021","journal-title":"J Neuroinflammation"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.expneurol.2016.09.005","article-title":"Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization","volume":"285","author":"Huang","year":"2016","journal-title":"Exp Neurol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"302","DOI":"10.1038\/nm.2107","article-title":"Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury","volume":"16","author":"Boulenguez","year":"2010","journal-title":"Nat Med"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"932487","DOI":"10.3389\/fphar.2022.932487","article-title":"Long-term administration of bumetanide improve functional recovery after spinal cord injury in rats","volume":"13","author":"Hashemizadeh","year":"2022","journal-title":"Front Pharmacol"},{"key":"ref29","first-page":"A-57","article-title":"Bumetanide promotes functional recovery of hindlimb function and reduces hemorrhage after spinal cord injury","volume":"36","author":"Johnston","year":"2019","journal-title":"J Neurotrauma"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"3406","DOI":"10.1089\/neu.2021.0219","article-title":"Hemorrhage and locomotor deficits induced by pain input after spinal cord injury are partially mediated by changes in Hemodynamics","volume":"38","author":"Strain","year":"2021","journal-title":"J Neurotrauma"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1161\/01.str.20.3.372","article-title":"Spinal cord blood flow and systemic blood pressure after experimental spinal cord injury in rats","volume":"20","author":"Guha","year":"1989","journal-title":"Stroke"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"10","DOI":"10.7554\/eLife.68015","article-title":"Topological network analysis of patient similarity for precision management of acute blood pressure in spinal cord injury","volume":"10","author":"Torres-Espin","year":"2021","journal-title":"eLife"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"665","DOI":"10.1016\/j.ccep.2017.08.002","article-title":"Cardiac innervation and the autonomic nervous system in sudden cardiac death","volume":"9","author":"Huang","year":"2017","journal-title":"Card Electrophysiol Clin"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"204","DOI":"10.4330\/wjc.v7.i4.204","article-title":"Autonomic and endocrine control of cardiovascular function","volume":"7","author":"Gordan","year":"2015","journal-title":"World J Cardiol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"164","DOI":"10.1016\/j.expneurol.2005.07.016","article-title":"Evidence that descending serotonergic systems protect spinal cord plasticity against the disruptive effect of uncontrollable stimulation","volume":"196","author":"Crown","year":"2005","journal-title":"Exp Neurol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"998","DOI":"10.1152\/jn.01160.2003","article-title":"Spinal neurons that express NK-1 receptors modulate descending controls that project through the dorsolateral funiculus","volume":"93","author":"Khasabov","year":"2005","journal-title":"J Neurophysiol"},{"key":"ref37","article-title":"Identifying the Descneding fiber Pathways that drive Secondary Tissue loss after spinal cord Injury","author":"Trevino","year":"2025"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"577264","DOI":"10.1016\/j.jneuroim.2020.577264","article-title":"Correlation between elevated inflammatory cytokines of spleen and spleen index in acute spinal cord injury","volume":"344","author":"Wu","year":"2020","journal-title":"J Neuroimmunol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1630","DOI":"10.1007\/s10753-019-01024-y","article-title":"Cellular inflammatory response of the spleen after acute spinal cord injury in rat","volume":"42","author":"Wu","year":"2019","journal-title":"Inflammation"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1089\/0897715041269641","article-title":"The role of excitotoxicity in secondary mechanisms of spinal cord injury: a review with an emphasis on the implications for white matter degeneration","volume":"21","author":"Park","year":"2004","journal-title":"J Neurotrauma"},{"key":"ref41","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1089\/neu.1997.14.81","article-title":"The effect of the sodium channel blocker QX-314 on recovery after acute spinal cord injury","volume":"14","author":"Agrawal","year":"1997","journal-title":"J Neurotrauma"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"1807","DOI":"10.1002\/glia.22559","article-title":"An increase in voltage-gated sodium channel current elicits microglial activation followed inflammatory responses in vitro and in vivo after spinal cord injury","volume":"61","author":"Jung","year":"2013","journal-title":"Glia"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"45316","DOI":"10.1038\/srep45316","article-title":"Neurotoxicity comparison of two types of local anaesthetics: amide-bupivacaine versus Ester-procaine","volume":"7","author":"Yu","year":"2017","journal-title":"Sci Rep"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2016\/9476020","article-title":"Cytokine and growth factor activation in vivo and in vitro after spinal cord injury","volume":"2016","author":"Garcia","year":"2016","journal-title":"Mediat Inflamm"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"181","DOI":"10.3171\/2008.10.SPINE08217","article-title":"Intrathecal pressure monitoring and cerebrospinal fluid drainage in acute spinal cord injury: a prospective randomized trial","volume":"10","author":"Kwon","year":"2009","journal-title":"J Neurosurg Spine"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1186\/s13049-015-0121-3","article-title":"Therapeutic hypothermia for acute brain injuries","volume":"23","author":"Andresen","year":"2015","journal-title":"Scand J Trauma Resusc Emerg Med"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"843","DOI":"10.3171\/2014.4.SPINE14330","article-title":"Hypothermia for spinal cord injury","volume":"21","author":"Ahmad","year":"2014","journal-title":"J Neurosurg Spine"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"186","DOI":"10.4103\/bc.bc_28_17","article-title":"Therapeutic hypothermia and targeted temperature management for traumatic brain injury: experimental and clinical experience","volume":"3","author":"Dietrich","year":"2017","journal-title":"Brain Circ"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"1585","DOI":"10.3390\/jcm11061585","article-title":"Hypothermia therapy for traumatic spinal cord injury: An updated review","volume":"11","author":"Ransom","year":"2022","journal-title":"J Clin Med"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1038\/nrneurol.2012.21","article-title":"Hypothermia for acute brain injury\u2014mechanisms and practical aspects","volume":"8","author":"Choi","year":"2012","journal-title":"Nat Rev Neurol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1038\/sc.2012.161","article-title":"Systemic hypothermia in acute cervical spinal cord injury: a case-controlled study","volume":"51","author":"Dididze","year":"2013","journal-title":"Spinal Cord"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"500","DOI":"10.1016\/j.jtcvs.2013.07.043","article-title":"Dexmedetomidine, an alpha-2a adrenergic agonist, promotes ischemic tolerance in a murine model of spinal cord ischemia-reperfusion","volume":"147","author":"Bell","year":"2014","journal-title":"J Thorac Cardiovasc Surg"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1016\/j.jocn.2009.05.041","article-title":"The effectiveness of dexmedetomidine in experimental spinal cord injury compared to methylprednisolone in rats","volume":"17","author":"Gul","year":"2010","journal-title":"J Clin Neurosci"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"1068","DOI":"10.1111\/j.1399-6576.2009.02019.x","article-title":"Effects of dexmedetomidine or methylprednisolone on inflammatory responses in spinal cord injury","volume":"53","author":"Can","year":"2009","journal-title":"Acta Anaesthesiol Scand"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"114349","DOI":"10.1016\/j.expneurol.2023.114349","article-title":"Protecting the injured central nervous system: do anesthesia or hypothermia ameliorate secondary injury?","volume":"363","author":"Davis","year":"2023","journal-title":"Exp Neurol"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"7197","DOI":"10.3390\/ijms23137197","article-title":"Preventive intrathecal injection of bupivacaine alleviated microglia activation and neuropathic pain in a rat model of chronic constriction injury","volume":"23","author":"Wu","year":"2022","journal-title":"Int J Mol Sci"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/s12871-015-0113-x","article-title":"Preemptive perineural bupivacaine attenuates the maintenance of mechanical and cold allodynia in a rat spinal nerve ligation model","volume":"15","author":"Clifford","year":"2015","journal-title":"BMC Anesthesiol"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1007\/BF03018241","article-title":"Intrathecal bupivacaine protects against extension of lesions in an acute photochemical spinal cord injury model","volume":"51","author":"Lopez","year":"2004","journal-title":"Can J Anaesth"},{"key":"ref59","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1089\/neur.2021.0055","article-title":"Noxious stimulation induces acute Hemorrhage and impairs long-term recovery after spinal cord injury (SCI) in female rats: evidence Estrous cycle may have a modulatory effect","volume":"3","author":"Baine","year":"2022","journal-title":"Neurotrauma Rep"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1880792\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:26:48Z","timestamp":1788236808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1880792\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,1]]},"references-count":59,"alternative-id":["10.3389\/fneur.2026.1880792"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1880792","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,1]]},"article-number":"1880792"}}