{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T05:24:44Z","timestamp":1786944284546,"version":"build-2736575974"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006769","name":"Russian Science Foundation","doi-asserted-by":"publisher","award":["24-15-00242"],"award-info":[{"award-number":["24-15-00242"]}],"id":[{"id":"10.13039\/501100006769","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Tricyclic antidepressants (TCAs) such as amitriptyline, desipramine, and clomipramine are widely used for the treatment of neuropathic pain, yet the cellular mechanisms underlying their analgesic effects remain incompletely understood. Increasing evidence suggests that, in addition to inhibiting monoamine reuptake, TCAs modulate neuronal calcium signaling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      As the sodiumcalcium exchanger (NCX) plays a key role in regulating intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dynamics and calcium-dependent desensitization of NMDA receptors, we investigated whether TCAs directly affect NCX activity. NCX transport currents were recorded using whole-cell patch-clamp in cultured rat cortical neurons, and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging was performed in HEK293 cells expressing NCX1 to assess Ca\n                      <jats:sup>2+<\/jats:sup>\n                      extrusion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Amitriptyline (10 \u03bcM) demonstrated the most prominent effect and significantly inhibited NCX-mediated currents by approximately 80% of the maximal block by Ni\n                      <jats:sup>2+<\/jats:sup>\n                      . The magnitude of inhibition was comparable to established NCX inhibitors, including KB-R7943 and SEA0400. Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging experiments demonstrated that amitriptyline slowed cytosolic Ca\n                      <jats:sup>2+<\/jats:sup>\n                      clearance in NCX1-expressing cells, indicating inhibition of the forward transport mode responsible for Ca\n                      <jats:sup>2+<\/jats:sup>\n                      extrusion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      These results provide direct evidence that amitriptyline inhibits NCX activity and alters neuronal Ca\n                      <jats:sup>2+<\/jats:sup>\n                      handling. This effect may contribute to enhanced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      -dependent desensitization of NMDA receptors and suppression of excitatory signaling, providing a mechanistic explanation of its analgetic properties.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1849383","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T04:37:03Z","timestamp":1786941423000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of sodium-calcium exchanger by tricyclic antidepressants"],"prefix":"10.3389","volume":"17","author":[{"given":"Sergei I.","family":"Boikov","sequence":"first","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences","place":["Saint-Petersburg, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatiana V.","family":"Karelina","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences","place":["Saint-Petersburg, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxim V.","family":"Nikolaev","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences","place":["Saint-Petersburg, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry A.","family":"Sibarov","sequence":"additional","affiliation":[{"name":"Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences","place":["Saint-Petersburg, Russia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1097\/AJP.0000000000000547","article-title":"A systematic review of NMDA receptor antagonists for treatment of neuropathic pain in clinical practice","volume":"34","author":"Aiyer","year":"2018","journal-title":"Clin. 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