{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T09:08:28Z","timestamp":1788858508949,"version":"build-2803163510"},"reference-count":62,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T00:00:00Z","timestamp":1788825600000},"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. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Neuropathic pain in diabetic patients is very difficult to treat and does not respond to conventional analgesic treatments. It has been observed that tricyclic antidepressants are able to reduce this type of pain. In some animal experimental models, drug combinations have yielded better results. Thus, this study analyzed the type of synergism produced by the combinations of Nortriptyline + Tramadol and Nortriptyline + Ibuprofen in streptozotocin-induced diabetic rats.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methodology<\/jats:title>\n                    <jats:p>Hyperglycemia was induced by administering 65\u00a0mg\/kg i.p. of streptozotocin to Wistar rats. The formalin model was used to evaluate hyperalgesia with administration of formalin at 0.5%. The effects of tramadol, ibuprofen, and nortriptyline as monotherapies were evaluated. The doses administered in combination were determined using the mean effective doses of each drug and the constant-ratio method. An isobolographic analysis was performed to determine the type of synergism.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nortriptyline, Tramadol, and Ibuprofen showed an antihyperalgesic effect dose-dependent. Nortriptyline was the most effective and most potent; its maximum effect was 96.67% \u00b1 1.52%, and the ED\n                      <jats:sub>50<\/jats:sub>\n                      was 3.0\u00a0mg\/kg. The Nortriptyline + Tramadol combination showed similar efficacy to that of Nortriptyline monotherapy. However, the ED\n                      <jats:sub>50<\/jats:sub>\n                      for its combination was significantly lower (0.97\u00a0mg\/kg). The isobolographic analysis showed that this combination generates supra-additive synergism, which was confirmed with the interaction index (\u03b3 = 0.237). The combination of Nortriptyline + Ibuprofeno exhibited a maxim effect of 81.36% \u00b1 2.36%, and the ED\n                      <jats:sub>50<\/jats:sub>\n                      was 15.6\u00a0mg\/kg, its interaction index was less than the unit (\u03b3 = 0.699) this indicates a supra-additive synergism.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study demonstrates that combinations of Nortriptyline with either Tramadol or Ibuprofen are more effective at lower doses than the drugs alone. A supra-additive synergism has been observed for both combinations, which may be useful in the management of neuropathic pain caused by diabetes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1814008","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T08:20:50Z","timestamp":1788855650000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Treatment of neuropathic pain in diabetic rats with synergistic combinations of nortriptyline + tramadol and nortriptyline + ibuprofen"],"prefix":"10.3389","volume":"17","author":[{"given":"M. Gicela","family":"P\u00e9rez-Hern\u00e1ndez","sequence":"first","affiliation":[{"name":"Faculty of Nursing, University of Colima","place":["Colima, Mexico"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Sesena-Rubfiaro","sequence":"additional","affiliation":[{"name":"Molecular Sciences, A.I. 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