{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T23:09:31Z","timestamp":1778540971809,"version":"3.51.4"},"reference-count":54,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T00:00:00Z","timestamp":1778544000000},"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. Toxicol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>While botulinum neurotoxin type E (BoNT\/E) has been shown to have analgesic effects in previous studies, the underlying mechanisms mediating its therapeutic effects remain incompletely understood. This study investigated the involvement of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the antinociceptive effects of BoNT\/E in a rat model of trigeminal neuropathic pain.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Neuropathic pain was induced in male Sprague\u2013Dawley rats through inferior alveolar nerve (IAN) injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>IAN injury significantly decreased air-puff thresholds, resulting in mechanical allodynia that persisted for up to 42 days. NLRP3 expression in the ipsilateral trigeminal ganglion (iTG) was significantly increased in the nerve-injured group on postoperative day (POD) 5. In contrast, subcutaneous administration of BoNT\/E (6 or 10\u00a0U\/kg) significantly attenuated mechanical allodynia and suppressed NLRP3 expression in the iTG on POD 5. Moreover, BoNT\/E (10\u00a0U\/kg) markedly reduced the elevated levels of inflammatory cytokines, including interleukin (IL)-1\u03b2, IL-18, tumor necrosis factor-alpha (TNF-\u03b1), and IL-6 in the iTG by IAN injury. The nerve-injured group also exhibited significant upregulation of hypoxia-inducible factor 1-alpha (HIF-1\u03b1) expression in the iTG, which was significantly decreased following BoNT\/E (10\u00a0U\/kg) treatment. Intraganglionic injection of PX-478, a HIF-1\u03b1 inhibitor, similarly attenuated mechanical allodynia, downregulated NLRP3 expression, and decreased IL-1\u03b2, IL-18, TNF-\u03b1, and IL-6 levels in the iTG.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Collectively, these findings demonstrate that modulation of the HIF-1\u03b1\u2013NLRP3 pathway in the iTG plays a critical regulatory role in neuropathic pain development and suggest that BoNT\/E may serve as a promising therapeutic strategy for managing chronic neuropathic pain.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/ftox.2026.1823460","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T22:10:25Z","timestamp":1778537425000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Botulinum toxin type E alleviates trigeminal neuropathic pain via modulation of the HIF-1\u03b1\u2013NLRP3 pathway"],"prefix":"10.3389","volume":"8","author":[{"given":"JoYoung","family":"Son","sequence":"first","affiliation":[{"name":"Department of Oral Physiology, School of Dentistry, Kyungpook National University","place":["Daegu, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YuMi","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, School of Dentistry, Kyungpook National University","place":["Daegu, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JinSook","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, School of Dentistry, Kyungpook National University","place":["Daegu, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JaeYoung","family":"Kim","sequence":"additional","affiliation":[{"name":"JETEMA Global","place":["Seongnam-si Gyeonggi-do, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"JeongSun","family":"Nam","sequence":"additional","affiliation":[{"name":"JETEMA Global","place":["Seongnam-si Gyeonggi-do, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"YoonKyoung","family":"Cha","sequence":"additional","affiliation":[{"name":"JETEMA Global","place":["Seongnam-si Gyeonggi-do, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"DongKuk","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, School of Dentistry, Kyungpook National University","place":["Daegu, Republic of Korea"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"25944","DOI":"10.1074\/jbc.M803756200","article-title":"SNAP-25 substrate peptide (residues 180-183) binds to but bypasses cleavage by catalytically active Clostridium botulinum neurotoxin E","volume":"283","author":"Agarwal","year":"2008","journal-title":"J. Biol. Chem."},{"key":"B2","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.pain.2005.07.017","article-title":"Role of peripheral group I and II metabotropic glutamate receptors in IL-1beta-induced mechanical allodynia in the orofacial area of conscious rats","volume":"118","author":"Ahn","year":"2005","journal-title":"Pain"},{"key":"B3","doi-asserted-by":"publisher","first-page":"395","DOI":"10.1016\/j.neuroscience.2010.04.059","article-title":"Acute neuroprotection by the synaptic blocker botulinum neurotoxin E in a rat model of focal cerebral ischaemia","volume":"169","author":"Antonucci","year":"2010","journal-title":"Neuroscience"},{"key":"B4","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1007\/s00702-004-0265-1","article-title":"Botulinum toxin type A in experimental neuropathic pain","volume":"112","author":"Bach-Rojecky","year":"2005","journal-title":"J. Neural. Transm. (Vienna)."},{"key":"B5","doi-asserted-by":"publisher","first-page":"S12","DOI":"10.1097\/00002508-200006001-00004","article-title":"Peripheral neuropathic pain: from mechanisms to symptoms","volume":"16","author":"Baron","year":"2000","journal-title":"Clin. J. Pain"},{"key":"B6","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1093\/bja\/aet127","article-title":"Sex differences in pain: a brief review of clinical and experimental findings","volume":"111","author":"Bartley","year":"2013","journal-title":"Br. J. Anaesth."},{"key":"B7","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1016\/j.cellimm.2016.06.002","article-title":"Hypoxia inducible factor 1\u03b1: a critical factor for the immune response to pathogens and leishmania","volume":"309","author":"Charpentier","year":"2016","journal-title":"Cell Immunol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1589","DOI":"10.1007\/s10787-023-01235-8","article-title":"The NLRP3 inflammasome: role in the pathobiology of chronic pain","volume":"31","author":"Chen","year":"2023","journal-title":"Inflammopharmacology"},{"key":"B9","doi-asserted-by":"publisher","first-page":"2070","DOI":"10.1016\/j.jpain.2022.08.004","article-title":"Cellular mechanisms mediating the antinociceptive effect of botulinum toxin A in a rodent model of trigeminal irritation by a foreign body","volume":"23","author":"Cho","year":"2022","journal-title":"J. Pain"},{"key":"B10","doi-asserted-by":"publisher","first-page":"f7656","DOI":"10.1136\/bmj.f7656","article-title":"Neuropathic pain: mechanisms and their clinical implications","volume":"348","author":"Cohen","year":"2014","journal-title":"BMJ"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1943","DOI":"10.1523\/JNEUROSCI.4402-04.2005","article-title":"Antiepileptic effects of botulinum neurotoxin E","volume":"25","author":"Costantin","year":"2005","journal-title":"J. Neurosci."},{"key":"B12","doi-asserted-by":"publisher","first-page":"106492","DOI":"10.1016\/j.intimp.2020.106492","article-title":"NLRP3 inflammasome is involved in nerve recovery after sciatic nerve injury","volume":"84","author":"Cui","year":"2020","journal-title":"Int. Immunopharmacol."},{"key":"B13","first-page":"169","article-title":"Gender differences in pain","volume":"14","author":"Dao","year":"2000","journal-title":"J. Orofac. Pain"},{"key":"B14","doi-asserted-by":"crossref","first-page":"20838","DOI":"10.1016\/S0021-9258(19)36861-9","article-title":"A role for the interchain disulfide or its participating thiols in the internalization of botulinum neurotoxin A revealed by a toxin derivative that binds to ecto-acceptors and inhibits transmitter release intracellularly","volume":"268","author":"de Paiva","year":"1993","journal-title":"J. Biol. Chem."},{"key":"B15","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1016\/j.toxicon.2020.02.020","article-title":"Clinical duration of action of different botulinum toxin types in humans","volume":"179","author":"Eleopra","year":"2020","journal-title":"Toxicon"},{"key":"B16","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1074\/jbc.M209821200","article-title":"Evaluation of the therapeutic usefulness of botulinum neurotoxin B, C1, E, and F compared with the long lasting type A basis for distinct durations of inhibition of exocytosis in central neurons","volume":"278","author":"Foran","year":"2002","journal-title":"J. Biol. Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.pnpbp.2011.10.007","article-title":"Blockade of microglial activation reduces mechanical allodynia in rats with compression of the trigeminal ganglion","volume":"36","author":"Han","year":"2012","journal-title":"Prog. Neuropsychopharmacol. Biol. Psychiatry"},{"key":"B18","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1186\/s12974-019-1459-7","article-title":"Microglial NLRP3 inflammasome activation mediates IL-1beta release and contributes to central sensitization in a recurrent nitroglycerin-induced migraine model","volume":"16","author":"He","year":"2019","journal-title":"J. Neuroinflammation"},{"key":"B19","doi-asserted-by":"publisher","first-page":"2903","DOI":"10.1002\/cne.23072","article-title":"Low-level laser therapy alleviates neuropathic pain and promotes function recovery in rats with chronic constriction injury: possible involvements in hypoxia-inducible factor 1alpha (HIF-1alpha)","volume":"520","author":"Hsieh","year":"2012","journal-title":"J. Comp. Neurol."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2114","DOI":"10.1038\/s41423-021-00740-6","article-title":"NLRP3 inflammasome activation and cell death","volume":"18","author":"Huang","year":"2021","journal-title":"Cell Mol. Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"1744806917719804","DOI":"10.1177\/1744806917719804","article-title":"Activation of NLRP3 inflammasome in peripheral nerve contributes to paclitaxel-induced neuropathic pain","volume":"13","author":"Jia","year":"2017","journal-title":"Mol. Pain"},{"key":"B22","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1038\/cmi2015.95","article-title":"Molecular mechanisms regulating NLRP3 inflammasome activation","volume":"13","author":"Jo","year":"2016","journal-title":"Cell Mol. Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"9179928","DOI":"10.1155\/2024\/9179928","article-title":"Blockade of Piezo2 pathway attenuates inflammatory and neuropathic pain in the orofacial area","volume":"2024","author":"Jo","year":"2024","journal-title":"Pain Res. Manag."},{"key":"B24","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.jim.2007.09.014","article-title":"Development of improved SNAP25 endopeptidase immuno-assays for botulinum type A and E toxins","volume":"329","author":"Jones","year":"2008","journal-title":"J. Immunol. Methods."},{"key":"B25","doi-asserted-by":"publisher","first-page":"130","DOI":"10.3390\/toxins17030130","article-title":"Can botulinum toxin type E serve as a novel therapeutic target for managing chronic orofacial pain?","volume":"17","author":"Jung","year":"2025","journal-title":"Toxins (Basel)."},{"key":"B26","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1016\/j.pain.2013.12.030","article-title":"Differential regulation of peripheral IL-1\u03b2-induced mechanical allodynia and thermal hyperalgesia in rats","volume":"155","author":"Kim","year":"2014","journal-title":"Pain"},{"key":"B27","doi-asserted-by":"publisher","first-page":"1173","DOI":"10.2147\/JPR.S249185","article-title":"Early blockade of EphA4 pathway reduces trigeminal neuropathic pain","volume":"13","author":"Kim","year":"2020","journal-title":"J. Pain Res."},{"key":"B28","doi-asserted-by":"publisher","first-page":"7677","DOI":"10.1073\/pnas.1400036111","article-title":"In vitro assay using engineered yeast vacuoles for neuronal SNARE-mediated membrane fusion","volume":"111","author":"Ko","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"B29","doi-asserted-by":"publisher","first-page":"e1108514","DOI":"10.1080\/2162402X","article-title":"EML4-ALK enhances programmed cell death-ligand 1 expression in pulmonary adenocarcinoma via hypoxia-inducible factor (HIF)-1alpha and STAT3","volume":"5","author":"Koh","year":"2015","journal-title":"Oncoimmunology"},{"key":"B30","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1002\/der2.155","article-title":"Botulinum toxin type E: a review","volume":"3","author":"Lebowitz","year":"2022","journal-title":"Dermatol. Rev."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/emm.2004.1","article-title":"Hypoxia-inducible factor (HIF-1) alpha: its protein stability and biological functions","volume":"36","author":"Lee","year":"2004","journal-title":"Exp. Mol. Med."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1744806919872602","DOI":"10.1177\/1744806919872602","article-title":"Central VEGF-A pathway plays a key role in the development of trigeminal neuropathic pain in rats","volume":"15","author":"Lee","year":"2019","journal-title":"Mol. Pain"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.neuroscience.2006.12.004","article-title":"Anti-allodynic efficacy of botulinum neurotoxin A in a model of neuropathic pain","volume":"145","author":"Luvisetto","year":"2007","journal-title":"Neuroscience"},{"key":"B34","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/j.coph.2004.12.006","article-title":"Botulinal neurotoxins: revival of an old killer","volume":"5","author":"Montecucco","year":"2005","journal-title":"Curr. Opin. Pharmacol."},{"key":"B35","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/bs.irn.2022.06.013","article-title":"Sex and gender differences in pain","volume":"164","author":"Osborne","year":"2022","journal-title":"Int. Rev. Neurobiol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"470","DOI":"10.1007\/BF03022619","article-title":"The effects of botulinum toxin A on mechanical and cold allodynia in a rat model of neuropathic pain","volume":"53","author":"Park","year":"2006","journal-title":"Can. J. Anaesth."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2959","DOI":"10.2147\/JPR.S222095","article-title":"Co-administered low doses of Ibuprofen and dexamethasone produce synergistic antinociceptive effects on neuropathic mechanical allodynia in rats","volume":"12","author":"Park","year":"2019","journal-title":"J. Pain Res."},{"key":"B38","doi-asserted-by":"publisher","first-page":"111344","DOI":"10.1016\/j.brainresbull.2025.111344","article-title":"BTX-A inhibited trigeminal neuralgia by blocking the NLRP3 pathway in rats","volume":"225","author":"Park","year":"2025","journal-title":"Brain Res. Bull."},{"key":"B39","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1124\/pr.116.012658","article-title":"Botulinum neurotoxins: biology, pharamacology, and toxicology","volume":"69","author":"Pirazzini","year":"2017","journal-title":"Pharmacol. Rev."},{"key":"B40","doi-asserted-by":"publisher","first-page":"116516","DOI":"10.1016\/j.jns.2019.116516","article-title":"Safety and pharmacodynamics of a novel recombinant botulinum toxin E (rBoNT-E): results of a phase 1 study in healthy Male subjects compared with abobotulinumtoxina (dysport\u00ae)","volume":"407","author":"Pons","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1038\/2280","article-title":"Mechanics of membrane fusion","volume":"5","author":"Rizo","year":"1998","journal-title":"Nat. Struct. Biol."},{"key":"B42","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/nrmicro3295","article-title":"Botulinum neurotoxins: genetic, structural and mechanistic insights","volume":"12","author":"Rossetto","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1204","DOI":"10.1038\/s41467-017-01269-x","article-title":"Thioredoxin-1 protects against androgen receptor-induced redox vulnerability in castration-resistant prostate cancer","volume":"8","author":"Samaranayake","year":"2017","journal-title":"Nat. Commun."},{"key":"B44","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1186\/s12974-021-02178-z","article-title":"Divanillyl sulfone suppresses NLRP3 inflammasome activation via inducing mitophagy to ameliorate chronic neuropathic pain in mice","volume":"18","author":"Shao","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"B45","doi-asserted-by":"publisher","first-page":"506","DOI":"10.3390\/ijms23010506","article-title":"TNF-\u03b1-Mediated RIPK1 pathway participates in the development of trigeminal neuropathic pain in rats","volume":"23","author":"Son","year":"2022","journal-title":"Int. J. Mol. Sci."},{"key":"B46","doi-asserted-by":"publisher","first-page":"477","DOI":"10.1038\/s41577-019-0165-0","article-title":"The NLRP3 inflammasome: molecular activation and regulation to therapeutics","volume":"19","author":"Swanson","year":"2019","journal-title":"Nat. Rev. Immunol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1186\/s10194-025-02191-0","article-title":"Altered expressions of CGRP, SULT1A1, HMGB1, and HIF-1alpha in the trigeminal ganglion in medication overuse headache in female rats","volume":"26","author":"Topa","year":"2025","journal-title":"J. Headache Pain"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1156","DOI":"10.1186\/s12903-024-04936-w","article-title":"Hypoxia-induced NLRP3 inflammasome activation via the HIF-1alpha\/NF-kappaB signaling pathway in human dental pulp fibroblasts","volume":"24","author":"Wang","year":"2024","journal-title":"BMC Oral Health"},{"key":"B49","doi-asserted-by":"publisher","first-page":"1510271","DOI":"10.3389\/fmed.2025.1510271","article-title":"The effect of ponicidin on CFA-induced chronic inflammatory pain and its mechanism based on network pharmacology and molecular docking","volume":"12","author":"Wang","year":"2025","journal-title":"Front. Med. (Lausanne)."},{"key":"B50","doi-asserted-by":"publisher","first-page":"1959","DOI":"10.1016\/S0140-6736(99)01307-0","article-title":"Neuropathic pain: aetiology, symptoms, mechanisms, and management","volume":"353","author":"Woolf","year":"1999","journal-title":"Lancet"},{"key":"B51","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.neuroscience.2018.12.030","article-title":"MiR-34c ameliorates neuropathic pain by targeting NLRP3 in a mouse model of chronic constriction injury","volume":"399","author":"Xu","year":"2019","journal-title":"Neuroscience"},{"key":"B52","doi-asserted-by":"publisher","first-page":"1183","DOI":"10.1177\/0022034516659278","article-title":"Antinociceptive effects of botulinum toxin type A on trigeminal neuropathic pain","volume":"95","author":"Yang","year":"2016","journal-title":"J. Dent. Res."},{"key":"B53","doi-asserted-by":"publisher","first-page":"847e","DOI":"10.1097\/PRS.0000000000005029","article-title":"Safety and efficacy of EB-001, a novel type E botulinum toxin, in subjects with glabellar frown lines: results of a phase 2, randomized, placebo-controlled, ascending-dose study","volume":"142","author":"Yoelin","year":"2018","journal-title":"Plast. Reconstr. Surg."},{"key":"B54","doi-asserted-by":"publisher","first-page":"1444","DOI":"10.1016\/j.jaci.2023.09.020","article-title":"Hypoxia-inducible factor 1\u03b1 activates the NLRP3 inflammasome to regulate epithelial differentiation in chronic rhinosinusitis","volume":"152","author":"Zhong","year":"2023","journal-title":"Allergy Clin. Immunol."}],"container-title":["Frontiers in Toxicology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1823460\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T22:10:26Z","timestamp":1778537426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/ftox.2026.1823460\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,12]]},"references-count":54,"alternative-id":["10.3389\/ftox.2026.1823460"],"URL":"https:\/\/doi.org\/10.3389\/ftox.2026.1823460","relation":{},"ISSN":["2673-3080"],"issn-type":[{"value":"2673-3080","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,12]]},"article-number":"1823460"}}