{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T13:35:50Z","timestamp":1785418550056,"version":"3.56.0"},"reference-count":50,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["RS-2022-NR070483"],"award-info":[{"award-number":["RS-2022-NR070483"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"award":["RS-2022-NR070483"],"award-info":[{"award-number":["RS-2022-NR070483"]}],"id":[{"id":"https:\/\/ror.org\/013aysd81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: While the functions of angiotensin-converting enzyme (ACE) 1 and 2 are well established in peripheral tissues, the role of the spinal ACE1 and ACE2 pathways in the development of neuropathic pain remains unclear. This study examined the role of the spinal ACE1 and ACE2 pathways in trigeminal neuropathic pain produced by inferior alveolar nerve (IAN) injury. Methods: The experiments were conducted using male Sprague-Dawley rats (6\u20138 weeks old, weighing 220\u2013250 g). The left mandibular second molar was extracted, and a dental mini-implant was placed to induce IAN injury. IAN injury produced robust and long-lasting mechanical allodynia and markedly increased angiotensinogen (AGT) expression within the ipsilateral trigeminal subnucleus caudalis (iTSC). Results: Neuropathic mechanical allodynia was inhibited by intracisternally administered losartan (an angiotensin II type-1 receptor antagonist), but not by an angiotensin II type-2 receptor antagonist. Intracisternal treatment with captopril (an ACE1 inhibitor) and diminazene aceturate (an ACE2 activator) produced significant anti-allodynic effects. Intracisternally injected angiotensin-(1-7) reduced neuropathic mechanical allodynia, and this anti-allodynic effect was blocked by pretreatment with A779, a Mas receptor inhibitor. In na\u00efve rats, the intracisternal administration of DX600 (an ACE2 inhibitor) resulted in mechanical allodynia, which was inhibited by intracisternal pretreatment with losartan. IAN injury led to upregulated ACE1 expression and downregulated ACE2 expression in the iTSC. Conclusions: Our findings indicate that IAN injury induces a polarized shift in the ACEs within the iTSC, characterized by increased ACE1 and decreased ACE2 expression. Their modulation may therefore offer a promising strategy for developing effective treatments for chronic pain.<\/jats:p>","DOI":"10.3390\/ph19050764","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:12:08Z","timestamp":1779455528000},"page":"764","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Differential Modulation of Spinal Angiotensin-Converting Enzymes Plays a Critical Role in the Development of Trigeminal Neuropathic Pain"],"prefix":"10.3390","volume":"19","author":[{"given":"Jo-Young","family":"Son","sequence":"first","affiliation":[{"name":"Department of Oral Physiology, Craniofacial Nerve-Bone Network Research Center, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Mi","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, Craniofacial Nerve-Bone Network Research Center, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Song-Hee","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, Craniofacial Nerve-Bone Network Research Center, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-Sook","family":"Ju","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, Craniofacial Nerve-Bone Network Research Center, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5570-2371","authenticated-orcid":false,"given":"Dong-Kuk","family":"Ahn","sequence":"additional","affiliation":[{"name":"Department of Oral Physiology, Craniofacial Nerve-Bone Network Research Center, School of Dentistry, Kyungpook National University, Daegu 41940, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/S0031-6997(24)01458-3","article-title":"International union of pharmacology XXIII. 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