{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T01:48:51Z","timestamp":1760233731125,"version":"build-2065373602"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T00:00:00Z","timestamp":1613260800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["MOST 109-2320-B-040-008-MY3","MOST 107-2320-B-040-024-"],"award-info":[{"award-number":["MOST 109-2320-B-040-008-MY3","MOST 107-2320-B-040-024-"]}]},{"DOI":"10.13039\/501100008641","name":"Chung Shan Medical University","doi-asserted-by":"publisher","award":["CSMU-INT-108-08","CSMU-INT-106-08"],"award-info":[{"award-number":["CSMU-INT-108-08","CSMU-INT-106-08"]}],"id":[{"id":"10.13039\/501100008641","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Recently, Toll-like receptors (TLRs), a family of pattern recognition receptors, are reported as potential modulators for neuropathic pain; however, the desired mechanism is still unexplained. Here, we operated on the sciatic nerve to establish a pre-clinical rodent model of chronic constriction injury (CCI) in Sprague-Dawley rats, which were assigned into CCI and Decompression groups randomly. In Decompression group, the rats were performed with nerve decompression at post-operative week 4. Mechanical hyperalgesia and mechanical allodynia were obviously attenuated after a month. Toll-like receptor 5 (TLR5)-immunoreactive (ir) expression increased in dorsal horn, particularly in the inner part of lamina II. Additionally, substance P (SP) and isolectin B4 (IB4)-ir expressions, rather than calcitonin-gene-related peptide (CGRP)-ir expression, increased in their distinct laminae. Double immunofluorescence proved that increased TLR5-ir expression was co-expressed mainly with IB4-ir expression. Through an intrathecal administration with FLA-ST Ultrapure (a TLR5 agonist, purified flagellin from Salmonella Typhimurium, only the CCI-induced mechanical hyperalgesia was attenuated dose-dependently. Moreover, we confirmed that mu-opioid receptor (MOR) and phospho-protein kinase C\u03b1 (pPKC\u03b1)-ir expressions but not phospho-protein kinase A RII (pPKA RII)-ir expression, increased in lamina II, where they mostly co-expressed with IB4-ir expression. Go 6976, a potent protein kinase C inhibitor, effectively reversed the FLA-ST Ultrapure- or DAMGO-mediated attenuated trend towards mechanical hyperalgesia by an intrathecal administration in CCI rats. In summary, our current findings suggest that nerve decompression improves CCI-induced mechanical hyperalgesia that might be through the cross-talk of TLR5 and MOR in a PKC\u03b1-dependent manner, which opens a novel opportunity for the development of analgesic therapeutics in neuropathic pain.<\/jats:p>","DOI":"10.3390\/ijms22041891","type":"journal-article","created":{"date-parts":[[2021,2,14]],"date-time":"2021-02-14T08:53:56Z","timestamp":1613292836000},"page":"1891","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Cross-Talk of Toll-Like Receptor 5 and Mu-Opioid Receptor Attenuates Chronic Constriction Injury-Induced Mechanical Hyperalgesia through a Protein Kinase C Alpha-Dependent Signaling"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1770-7849","authenticated-orcid":false,"given":"Ching","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Anatomy, School of Medicine, Chung Shan Medical University, 40201 Taichung, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-Kai","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, Chung Shan Medical University, 40201 Taichung, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3978-5576","authenticated-orcid":false,"given":"Chao-Bin","family":"Yeh","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, Chung Shan Medical University Hospital, 40201 Taichung, Taiwan"},{"name":"Department of Emergency Medicine, School of Medicine, Chung Shan Medical University, 40201 Taichung, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming-Lin","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, Chung Shan Medical University, 40201 Taichung, Taiwan"},{"name":"Department of Medical Education, Chung Shan Medical University Hospital, 40201 Taichung, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wen-Chieh","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, Chung Shan Medical University, 40201 Taichung, Taiwan"},{"name":"Department of Medical Education, Chung Shan Medical University Hospital, 40201 Taichung, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiung-Hui","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, Chung Shan Medical University, 40201 Taichung, Taiwan"},{"name":"Department of Medical Education, Chung Shan Medical University Hospital, 40201 Taichung, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"To-Jung","family":"Tseng","sequence":"additional","affiliation":[{"name":"Department of Anatomy, School of Medicine, Chung Shan Medical University, 40201 Taichung, Taiwan"},{"name":"Department of Medical Education, Chung Shan Medical University Hospital, 40201 Taichung, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,2,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17002","DOI":"10.1038\/nrdp.2017.2","article-title":"Neuropathic pain","volume":"3","author":"Colloca","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev.neuro.051508.135531","article-title":"Neuropathic pain: A maladaptive response of the nervous system to damage","volume":"32","author":"Costigan","year":"2009","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1016\/S1474-4422(16)30231-9","article-title":"Carpal tunnel syndrome: Clinical features, diagnosis and management","volume":"15","author":"Padua","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/S1474-4422(17)30059-5","article-title":"Diagnosis and treatment of carpal tunnel syndrome","volume":"16","author":"Thomson","year":"2017","journal-title":"Lancet Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1016\/j.pain.2010.09.030","article-title":"Central sensitization: Implications for the diagnosis and treatment of pain","volume":"152","author":"Woolf","year":"2011","journal-title":"Pain"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1212\/WNL.0000000000002478","article-title":"Dorsal horn circuitry: Complexity and implications for mechanisms of neuropathic pain","volume":"86","author":"Benarroch","year":"2016","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/j.cell.2009.09.028","article-title":"Cellular and molecular mechanisms of pain","volume":"139","author":"Bassam","year":"2009","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1007\/s12640-017-9799-5","article-title":"Nerve decompression improves spinal synaptic plasticity of opioid receptors for pain relief","volume":"33","author":"Tseng","year":"2018","journal-title":"Neurotox. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1016\/j.pain.2009.12.012","article-title":"Classification of nociceptors--to what purpose?","volume":"148","author":"Handwerker","year":"2010","journal-title":"Pain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/j.neuroscience.2008.08.010","article-title":"Influences of surgical decompression on the dorsal horn after chronic constriction injury: Changes in peptidergic and delta-opioid receptor(+) nerve terminals","volume":"156","author":"Tseng","year":"2008","journal-title":"Neuroscience"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0304-3959(88)90209-6","article-title":"A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man","volume":"33","author":"Bennett","year":"1988","journal-title":"Pain"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0304-3959(90)91074-S","article-title":"A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury","volume":"43","author":"Seltzer","year":"1990","journal-title":"Pain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/S0304-3959(00)00276-1","article-title":"Spared nerve injury: An animal model of persistent peripheral neuropathic pain","volume":"87","author":"Decosterd","year":"2000","journal-title":"Pain"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.pharmthera.2017.10.006","article-title":"Toll-like receptors and their role in persistent pain","volume":"184","author":"Lacagnina","year":"2018","journal-title":"Pharmacol. Ther."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1007\/s12264-012-1219-5","article-title":"Emerging role of Toll-like receptors in the control of pain and itch","volume":"28","author":"Liu","year":"2012","journal-title":"Neurosci. Bull."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1016\/j.expneurol.2011.09.038","article-title":"Toll-like receptors in chronic pain","volume":"234","author":"Nicotra","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1186\/1742-2094-10-148","article-title":"Toll-like receptor signaling adapter proteins govern spread of neuropathic pain and recovery following nerve injury in male mice","volume":"10","author":"Stokes","year":"2013","journal-title":"J. Neuroinflammation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1183\/09031936.00171908","article-title":"PKC(alpha) and PKC(epsilon) differentially regulate Legionella pneumophila-induced GM-CSF","volume":"34","author":"Vardarova","year":"2009","journal-title":"Eur. Respir. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1326","DOI":"10.1038\/nm.3978","article-title":"Inhibition of mechanical allodynia in neuropathic pain by TLR5-mediated A-fiber blockade","volume":"21","author":"Xu","year":"2015","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"34356","DOI":"10.1038\/srep34356","article-title":"Interferon alpha inhibits spinal cord synaptic and nociceptive transmission via neuronal-glial interactions","volume":"6","author":"Liu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1186\/1742-2094-10-112","article-title":"Different TLR4 expression and microglia\/macrophage activation induced by hemorrhage in the rat spinal cord after compressive injury","volume":"10","author":"Zhang","year":"2013","journal-title":"J. Neuroinflammation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"273","DOI":"10.3389\/fnmol.2019.00273","article-title":"Internalized GPCRs as potential therapeutic targets for the management of pain","volume":"12","author":"Retamal","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1016\/j.neuropharm.2013.03.039","article-title":"Opioids and their receptors: Are we there yet?","volume":"76","author":"Pasternak","year":"2014","journal-title":"Neuropharmacology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.neuropharm.2019.03.006","article-title":"Bifunctional opioid receptor ligands as novel analgesics","volume":"151","author":"Cunningham","year":"2019","journal-title":"Neuropharmacology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.3389\/fphar.2020.01078","article-title":"Mu opioid receptor heterodimers emerge as novel therapeutic targets: Recent progress and future perspective","volume":"11","author":"Zhang","year":"2020","journal-title":"Front. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Melkes, B., Markova, V., Hejnova, L., and Novotny, J. (2020). beta-Arrestin 2 and ERK1\/2 are important mediators engaged in close cooperation between TRPV1 and -opioid receptors in the plasma membrane. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21134626"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"12072","DOI":"10.1073\/pnas.1222044110","article-title":"Identification of a \u03bc-\u03b4 opioid receptor heteromer-biased agonist with antinociceptive activity","volume":"110","author":"Gomes","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"842","DOI":"10.1097\/j.pain.0000000000001768","article-title":"Activation of \u03bc-\u03b4 opioid receptor heteromers inhibits neuropathic pain behavior in rodents","volume":"161","author":"Tiwari","year":"2020","journal-title":"Pain"},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"29 Belcheva, M.M., Vogel, Z., Ignatova, E., Avidor-Reiss, T., Zippel, R., Levy, R., Young, E.C., Barg, J., and Coscia, C.J. (1998). Opioid modulation of extracellular signal-regulated protein kinase activity is ras dependent and involves Gbetagamma subunits. J. Neurochem., 70, 635\u2013645.","DOI":"10.1046\/j.1471-4159.1998.70020635.x"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1016\/j.lfs.2003.09.038","article-title":"Synergistic interactions between cannabinoid and opioid analgesics","volume":"74","author":"Cichewicz","year":"2004","journal-title":"Life Sci."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1038\/sj.bjp.0706757","article-title":"Mu opioid and CB1 cannabinoid receptor interactions: Reciprocal inhibition of receptor signaling and neuritogenesis","volume":"148","author":"Rios","year":"2006","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1002\/cne.21311","article-title":"Modification of classical neurochemical markers in identified primary afferent neurons with Abeta-, Adelta- and C-fibers after chronic constriction injury in mice","volume":"502","author":"Ruscheweyh","year":"2007","journal-title":"J. Comp. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.expneurol.2009.01.014","article-title":"Nociceptive responses and spinal plastic changes of afferent C-fibers in three neuropathic pain models induced by sciatic nerve injury in the rat","volume":"217","author":"Navarro","year":"2009","journal-title":"Exp. Neurol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"5715","DOI":"10.1007\/s12035-019-1494-5","article-title":"Non-peptidergic nociceptive neurons are essential for mechanical inflammatory hypersensitivity in mice","volume":"56","author":"Pinto","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1002\/jcb.27269","article-title":"MicroRNA-217 relieved neuropathic pain through targeting toll-like receptor 5 expression","volume":"120","author":"Jiang","year":"2019","journal-title":"J. Cell Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"5238730","DOI":"10.1155\/2016\/5238730","article-title":"Blockade of Toll-like receptors (TLR2, TLR4) attenuates pain and potentiates Buprenorphine analgesia in a rat neuropathic pain model","volume":"2016","author":"Jurga","year":"2016","journal-title":"Neural Plast."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1002\/jcb.27088","article-title":"LncRNA X inactive specific transcript contributes to neuropathic pain development by sponging miR-154-5p via inducing toll-like receptor 5 in CCI rat models","volume":"120","author":"Wei","year":"2019","journal-title":"J. Cell Biochem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1016\/j.celrep.2016.09.076","article-title":"HMGB1 activates proinflammatory signaling via TLR5 leading to allodynia","volume":"17","author":"Das","year":"2016","journal-title":"Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"672395","DOI":"10.1155\/2010\/672395","article-title":"DAMPening inflammation by modulating TLR signalling","volume":"2010","author":"Piccinini","year":"2010","journal-title":"Mediators Inflamm."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.neuropharm.2017.10.014","article-title":"Mechanisms of mu-opioid receptor inhibition of NMDA receptor-induced substance P release in the rat spinal cord","volume":"128","author":"Chen","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1016\/j.neuroscience.2010.08.035","article-title":"Mu and delta opioid receptors on nociceptors attenuate mechanical hyperalgesia in rat","volume":"171","author":"Joseph","year":"2010","journal-title":"Neuroscience"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"7338","DOI":"10.1007\/s12035-019-1607-1","article-title":"Simultaneous Activation of Mu and Delta Opioid Receptors Reduces Allodynia and Astrocytic Connexin 43 in an Animal Model of Neuropathic Pain","volume":"56","author":"Vicario","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.pain.2005.05.035","article-title":"Peripheral axonal injury results in reduced mu opioid receptor pre- and post-synaptic action in the spinal cord","volume":"117","author":"Kohno","year":"2005","journal-title":"Pain"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1016\/j.pain.2008.01.004","article-title":"Peripherally acting mu-opioid receptor agonist attenuates neuropathic pain in rats after L5 spinal nerve injury","volume":"138","author":"Guan","year":"2008","journal-title":"Pain"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1002\/jcb.29322","article-title":"Protein kinase C-\u03b1 upregulates sodium channel Nav1.9 in nociceptive dorsal root ganglion neurons in an inflammatory arthritis pain model of rat","volume":"121","author":"Bai","year":"2020","journal-title":"J. Cell Biochem."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"10285","DOI":"10.1038\/s41598-018-28512-9","article-title":"Spinal PKC\u03b1 inhibition and gene-silencing for pain relief: AMPAR trafficking at the synapses between primary afferents and sensory interneurons","volume":"8","author":"Kopach","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1097\/ALN.0b013e3182390788","article-title":"Isozyme-specific effects of protein kinase C in pain modulation","volume":"115","author":"Zhao","year":"2011","journal-title":"Anesthesiology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1016\/j.phrs.2007.04.006","article-title":"Protein kinase C in pain: Involvement of multiple isoforms","volume":"55","author":"Mohammad","year":"2007","journal-title":"Pharmacol. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1146\/annurev-neuro-080317-061522","article-title":"Endogenous and exogenous opioids in pain","volume":"41","author":"Corder","year":"2018","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"R1","DOI":"10.1016\/0014-2999(95)00322-C","article-title":"Inhibition of protein kinase C but not of protein kinase A, blocks the development of acute antinociceptive tolerance to an intrathecally administered \u03bc-opioid receptor agonist in the mouse","volume":"280","author":"Narita","year":"1995","journal-title":"Eur. J. Pharmacol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"3400","DOI":"10.4049\/jimmunol.1202658","article-title":"Morphine prevents lipopolysaccharide-induced TNF secretion in mast cells blocking I\u03baB kinase activation and SNAP-23 phosphorylation: Correlation with the formation of a \u03b2-arrestin\/TRAF6 complex","volume":"191","author":"Cruz","year":"2013","journal-title":"J. Immunol."},{"key":"ref_52","first-page":"6325","article-title":"Role of nociceptor Toll-like receptor 4 (TLR4) in opioid-induced hyperalgesia and hyperalgesic priming","volume":"109","author":"Araldi","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"6325","DOI":"10.1073\/pnas.1200130109","article-title":"Morphine activates neuroinflammation in a manner parallel to endotoxin","volume":"109","author":"Wang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"L267","DOI":"10.1152\/ajplung.00100.2006","article-title":"Legionella pneumophila-induced PKCalpha-, MAPK- and NF-kappaB-dependent COX-2 expression in human lung epithelium","volume":"292","author":"Etouem","year":"2007","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/0304-3959(83)90201-4","article-title":"Ethical guidelines for investigations of experimental pain in conscious animals","volume":"16","author":"Zimmermann","year":"1983","journal-title":"Pain"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1016\/j.ejphar.2018.03.006","article-title":"Valnoctamide: The effect on relieving of neuropathic pain and possible mechanisms","volume":"827","author":"Samur","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"3069","DOI":"10.1093\/cercor\/bht162","article-title":"Cortical PKC inhibition promotes axonal regeneration of the corticospinal tract and forelimb functional recovery after cervical dorsal spinal hemisection in adult rats Cereb","volume":"24","author":"Wang","year":"2014","journal-title":"Cortex"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1213\/01.ane.0000226100.46866.ea","article-title":"Intermittent lumbar puncture in rats: A novel method for the experimental study of opioid tolerance","volume":"103","author":"Xu","year":"2006","journal-title":"Anesth. Analg."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1891\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:24:12Z","timestamp":1760160252000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/4\/1891"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,2,14]]},"references-count":58,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,2]]}},"alternative-id":["ijms22041891"],"URL":"https:\/\/doi.org\/10.3390\/ijms22041891","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2021,2,14]]}}}