{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T22:27:53Z","timestamp":1787610473813,"version":"build-2736575974"},"reference-count":31,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T00:00:00Z","timestamp":1741910400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Croatian Research Foundation","award":["HRZZ UIP-2019-04-8277"],"award-info":[{"award-number":["HRZZ UIP-2019-04-8277"]}]},{"name":"Croatian Research Foundation","award":["DOK-2021-02-6169"],"award-info":[{"award-number":["DOK-2021-02-6169"]}]},{"name":"Croatian Research Foundation","award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}]},{"name":"European Regional Development Fund, Operational Program Competitiveness and Cohesion","award":["HRZZ UIP-2019-04-8277"],"award-info":[{"award-number":["HRZZ UIP-2019-04-8277"]}]},{"name":"European Regional Development Fund, Operational Program Competitiveness and Cohesion","award":["DOK-2021-02-6169"],"award-info":[{"award-number":["DOK-2021-02-6169"]}]},{"name":"European Regional Development Fund, Operational Program Competitiveness and Cohesion","award":["KK.01.1.1.02.0021"],"award-info":[{"award-number":["KK.01.1.1.02.0021"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Toxins"],"abstract":"<jats:p>Botulinum toxin type A (BoNT-A) induces a bilateral analgesic effect following unilateral injection in rodent bilateral or mirror pain models. This occurs either by indirect plasticity-related actions, or by the toxin\u2019s direct central action in bilateral spinal circuits. Herein, we aimed to resolve this question by assessing the role of trans-synaptic toxin traffic in a bilateral inflammatory pain model. The analgesic effect of the toxin was examined in rats pre-treated with unilateral intraplantar BoNT-A (7 U\/kg) and subsequently challenged with bilateral carrageenan-evoked hind-paw inflammation (2%, 50 \u00b5L\/paw, 6 days post BoNT-A). Specific neutralizing antitoxin injected into the lumbar intrathecal space (2 IU, 24 h post BoNT-A), aimed at preventing the spinal trans-synaptic traffic of BoNT-A, abolished its bilateral analgesic effect. The toxin trans-synaptic effect was associated with reduced c-Fos neuronal activation and BoNT-A-mediated cleavage of synaptosomal-associated protein 25 (SNAP-25) in the bilateral dorsal horn. Here, we showed that, in bilaterally occurring pain, BoNT-A exerts a direct contralateral analgesic action extending beyond the level of the dorsal root ganglion sensory neuron that directly links the hindlimb injection site to the primary sensory region. This points to the crucial role of the toxin\u2019s central trans-synaptic traffic, and its direct action at propriospinal nociceptive circuits in its pain-relieving efficacy.<\/jats:p>","DOI":"10.3390\/toxins17030140","type":"journal-article","created":{"date-parts":[[2025,3,14]],"date-time":"2025-03-14T13:07:51Z","timestamp":1741957671000},"page":"140","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Botulinum Toxin Type A Exerts Direct Trans-Synaptic Action at Bilateral Spinal Nociceptive Circuits"],"prefix":"10.3390","volume":"17","author":[{"given":"Dalia","family":"Nemani\u0107","sequence":"first","affiliation":[{"name":"Department of Pharmacology, University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kova\u010di\u0107a 1, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6521-4948","authenticated-orcid":false,"given":"Petra","family":"\u0160o\u0161tari\u0107","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Croatian Institute of Brain Research, University of Zagreb School of Medicine, \u0160alata 11, 10 000 Zagreb, Croatia"},{"name":"Department of Neuroscience, Karolinska Institutet, Solnavagen 9\u2013kvarter B4, 17165 Solna, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7016-1853","authenticated-orcid":false,"given":"Patrik","family":"Megli\u0107","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Croatian Institute of Brain Research, University of Zagreb School of Medicine, \u0160alata 11, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivica","family":"Matak","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Croatian Institute of Brain Research, University of Zagreb School of Medicine, \u0160alata 11, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4580-833X","authenticated-orcid":false,"given":"Lidija","family":"Bach-Rojecky","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, University of Zagreb Faculty of Pharmacy and Biochemistry, A. Kova\u010di\u0107a 1, 10 000 Zagreb, Croatia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1521","DOI":"10.1007\/s00204-022-03271-9","article-title":"Toxicology and pharmacology of botulinum and tetanus neurotoxins: An update","volume":"96","author":"Pirazzini","year":"2022","journal-title":"Arch. 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