{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T16:40:08Z","timestamp":1751733608960,"version":"3.41.0"},"reference-count":40,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2018,8,2]],"date-time":"2018-08-02T00:00:00Z","timestamp":1533168000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"National Science and Technology Major Project for \u2018Major New Drugs Innovation & Development\u2019","award":["2014ZX09507003-004"],"award-info":[{"award-number":["2014ZX09507003-004"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["European Journal of Pain"],"published-print":{"date-parts":[[2019,1]]},"abstract":"Abstract<\/jats:title>Background<\/jats:title>A combination of analgesic agents with different mechanisms can induce additive or synergistic analgesia. The N\u2010type voltage\u2010dependent calcium channel (N\u2010VDCC<\/jats:styled-content>) is a novel therapeutic target for pain control. In addition to providing effective pain relief when used alone, N\u2010VDCC<\/jats:styled-content>blockers produce synergistic analgesia when used in combination with opiates. However, the interaction between N\u2010VDCC<\/jats:styled-content>blockers and nonsteroidal anti\u2010inflammatory drugs (NSAID<\/jats:styled-content>s) remains unclear.<\/jats:p><\/jats:sec>Methods<\/jats:title>Using isobolographic analysis and composite additive curve analysis, the antinociceptive interaction betweenZC<\/jats:styled-content>88, a selective N\u2010VDCC<\/jats:styled-content>blocker and ibuprofen, a classicalNSAID<\/jats:styled-content>, was investigated in two mouse models of visceral and somatic inflammatory pain.<\/jats:p><\/jats:sec>Results<\/jats:title>In the acetic acid writhing test, bothZC<\/jats:styled-content>88 (10.5\u201342\u00a0mg\/kg, intraperitoneally) and ibuprofen (50\u2013200\u00a0mg\/kg, orally) produced dose\u2010dependent antinociception, withED<\/jats:styled-content>50<\/jats:sub>values of 27.2 and 100.5\u00a0mg\/kg, respectively.ZC<\/jats:styled-content>88 in combination with ibuprofen (ZC<\/jats:styled-content>88\u00a0+\u00a0ibuprofen) also induced significant antinociception, and isobolographic analysis revealed a synergistic interaction at 50% effect level. The experimentalED<\/jats:styled-content>50<\/jats:sub>(ED<\/jats:styled-content>50 mix<\/jats:sub>) of this combination (34.5\u00a0mg\/kg) was significantly lower than the theoreticalED<\/jats:styled-content>50<\/jats:sub>(ED<\/jats:styled-content>50 add<\/jats:sub>; 63.8\u00a0mg\/kg). Additionally, composite additive curve analysis displayed synergistic interaction at other effect levels. In the formalin test,ZC<\/jats:styled-content>88 or ibuprofen alone significantly reduced late\u2010phase rather than early\u2010phase pain, withED<\/jats:styled-content>50<\/jats:sub>values of 31.3 and 123.9\u00a0mg\/kg, respectively. Similarly, both isobolographic analysis and composite additive curve analysis revealed synergistic antinociception ofZC<\/jats:styled-content>88\u00a0+\u00a0ibuprofen (40.6\u00a0mg\/kg ofED<\/jats:styled-content>50 mix<\/jats:sub>vs. 77.6\u00a0mg\/kg ofED<\/jats:styled-content>50 add<\/jats:sub>).<\/jats:p><\/jats:sec>Conclusion<\/jats:title>ZC<\/jats:styled-content>88 in combination with ibuprofen produces synergistic antinociception in mouse models of somatic and visceral inflammatory pain.<\/jats:p><\/jats:sec>Significance<\/jats:title>BecauseZC<\/jats:styled-content>88\u00a0+\u00a0ibuprofen achieves the same antinociceptive effect at lower doses, the use of this combination could result in fewer dose\u2010related untoward effects. The potentiation ofZC<\/jats:styled-content>88 on ibuprofen\u2010induced antinociception indicates that N\u2010VDCC<\/jats:styled-content>blocker has potential benefit to treat severe inflammatory pain.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ejp.1281","type":"journal-article","created":{"date-parts":[[2018,7,6]],"date-time":"2018-07-06T05:38:47Z","timestamp":1530855527000},"page":"46-56","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synergistic antinociception betweenZC<\/scp>88, an N\u2010type voltage\u2010dependent calcium channel blocker, and ibuprofen in mouse models of visceral and somatic inflammatory pain"],"prefix":"10.1002","volume":"23","author":[{"given":"W.\u2010Z.","family":"Zhou","sequence":"first","affiliation":[{"name":"Beijing Key Laboratory of Neuropsychopharmacology State Key Laboratory of Toxicology and Medical Countermeasures Beijing Institute of Pharmacology and Toxicology 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