{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T01:38:08Z","timestamp":1784770688157,"version":"3.55.0"},"reference-count":39,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T00:00:00Z","timestamp":1633392000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education, Culture, Sports, Science and Technology of Japan","award":["No. 18H02992, No. 17K01358 and No. 20K12648"],"award-info":[{"award-number":["No. 18H02992, No. 17K01358 and No. 20K12648"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Peripheral nerve injury leads to sensory ganglion hyperexcitation, which increases neurotransmitter release and neuropathic pain. Botulinum toxin type A (BoNT\/A) regulates pain transmission by reducing neurotransmitter release, thereby attenuating neuropathic pain. Despite multiple studies on the use of BoNT\/A for managing neuropathic pain in the orofacial region, its exact mechanism of transport remains unclear. In this study, we investigated the effects of BoNT\/A in managing neuropathic pain in two different animal models and its transport mechanism in the trigeminal nerve. Intraperitoneal administration of cisplatin induced bilateral neuropathic pain in the orofacial region, reducing the head withdrawal threshold to mechanical stimulation. Unilateral infraorbital nerve constriction (IONC) also reduced the ipsilateral head withdrawal threshold to mechanical stimulation. Unilateral peripheral administration of BoNT\/A to the rat whisker pad attenuated cisplatin-induced pain behavior bilaterally. Furthermore, contralateral peripheral administration of BoNT\/A attenuated neuropathy-induced behavior caused by IONC. We also noted the presence of BoNT\/A in the blood using the mouse bioassay. In addition, the Alexa Fluor-488-labeled C-terminal half of the heavy chain of BoNT\/A (BoNT\/A-Hc) was localized in the neurons of the bilateral trigeminal ganglia following its unilateral administration. These findings suggest that axonal and hematogenous transport are involved in the therapeutic effects of peripherally administered BoNT\/A in the orofacial region.<\/jats:p>","DOI":"10.3390\/toxins13100704","type":"journal-article","created":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T01:59:47Z","timestamp":1633917587000},"page":"704","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Peripherally Administered Botulinum Toxin Type A Localizes Bilaterally in Trigeminal Ganglia of Animal Model"],"prefix":"10.3390","volume":"13","author":[{"given":"Arief","family":"Waskitho","sequence":"first","affiliation":[{"name":"Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumiko","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Bacteriology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Swarnalakshmi","family":"Raman","sequence":"additional","affiliation":[{"name":"Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fumiya","family":"Kano","sequence":"additional","affiliation":[{"name":"Department of Tissue Regeneration, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijiao","family":"Yan","sequence":"additional","affiliation":[{"name":"Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Resmi","family":"Raju","sequence":"additional","affiliation":[{"name":"Department of Oral Disease Research, National Center for Geriatrics and Gerontology, Obu 474-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaista","family":"Afroz","sequence":"additional","affiliation":[{"name":"Department of Prosthodontics, ZA Dental College, Aligarh Muslim University, Aligarh 202002, India"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tsuyoshi","family":"Morita","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Anatomy, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Ikutame","sequence":"additional","affiliation":[{"name":"Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7079-5596","authenticated-orcid":false,"given":"Kazuo","family":"Okura","sequence":"additional","affiliation":[{"name":"Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masamitsu","family":"Oshima","sequence":"additional","affiliation":[{"name":"Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akihito","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Department of Tissue Regeneration, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otto","family":"Baba","sequence":"additional","affiliation":[{"name":"Department of Oral and Maxillofacial Anatomy, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1069-2605","authenticated-orcid":false,"given":"Yoshizo","family":"Matsuka","sequence":"additional","affiliation":[{"name":"Department of Stomatognathic Function and Occlusal Reconstruction, Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8504, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1227","DOI":"10.3389\/fnins.2019.01227","article-title":"Peripheral and Central Mechanisms of Persistent Orofacial Pain","volume":"13","author":"Shinoda","year":"2019","journal-title":"Front. 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