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Synergistic antinociception between ZC 88, an N‐type voltage‐dependent calcium channel blocker, and ibuprofen in mouse models of visceral and somatic inflammatory pain
Author(s) -
Zhou W.Z.,
Zhao T.Y.,
Wang Z.Y.,
Lu G.Y.,
Zhang S.Z.,
Zhang C.,
Wu N.,
Li J.
Publication year - 2019
Publication title -
european journal of pain
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.305
H-Index - 109
eISSN - 1532-2149
pISSN - 1090-3801
DOI - 10.1002/ejp.1281
Subject(s) - ibuprofen , pharmacology , analgesic , visceral pain , chemistry , nociception , calcium channel , calcium channel blocker , voltage dependent calcium channel , area under the curve , medicine , calcium , receptor , biochemistry , organic chemistry
Background A combination of analgesic agents with different mechanisms can induce additive or synergistic analgesia. The N‐type voltage‐dependent calcium channel (N‐ VDCC ) is a novel therapeutic target for pain control. In addition to providing effective pain relief when used alone, N‐ VDCC blockers produce synergistic analgesia when used in combination with opiates. However, the interaction between N‐ VDCC blockers and nonsteroidal anti‐inflammatory drugs ( NSAID s) remains unclear. Methods Using isobolographic analysis and composite additive curve analysis, the antinociceptive interaction between ZC 88, a selective N‐ VDCC blocker and ibuprofen, a classical NSAID , was investigated in two mouse models of visceral and somatic inflammatory pain. Results In the acetic acid writhing test, both ZC 88 (10.5–42 mg/kg, intraperitoneally) and ibuprofen (50–200 mg/kg, orally) produced dose‐dependent antinociception, with ED 50 values of 27.2 and 100.5 mg/kg, respectively. ZC 88 in combination with ibuprofen ( ZC 88 + ibuprofen) also induced significant antinociception, and isobolographic analysis revealed a synergistic interaction at 50% effect level. The experimental ED 50 ( ED 50 mix ) of this combination (34.5 mg/kg) was significantly lower than the theoretical ED 50 ( ED 50 add ; 63.8 mg/kg). Additionally, composite additive curve analysis displayed synergistic interaction at other effect levels. In the formalin test, ZC 88 or ibuprofen alone significantly reduced late‐phase rather than early‐phase pain, with ED 50 values of 31.3 and 123.9 mg/kg, respectively. Similarly, both isobolographic analysis and composite additive curve analysis revealed synergistic antinociception of ZC 88 + ibuprofen (40.6 mg/kg of ED 50 mix vs. 77.6 mg/kg of ED 50 add ). Conclusion ZC 88 in combination with ibuprofen produces synergistic antinociception in mouse models of somatic and visceral inflammatory pain. Significance Because ZC 88 + ibuprofen achieves the same antinociceptive effect at lower doses, the use of this combination could result in fewer dose‐related untoward effects. The potentiation of ZC 88 on ibuprofen‐induced antinociception indicates that N‐ VDCC blocker has potential benefit to treat severe inflammatory pain.