Synergistic antinociception between ZC88, an N-type voltage-dependent calcium channel blocker, and ibuprofen in mouse models of visceral and somatic inflammatory pain.

Abstract

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 (NSAIDs) remains unclear. Using isobolographic analysis and composite additive curve analysis, the antinociceptive interaction between ZC88, a selective N-VDCC blocker and ibuprofen, a classical NSAID, was investigated in two mouse models of visceral and somatic inflammatory pain. In the acetic acid writhing test, both ZC88 (10.5-42mg/kg, intraperitoneally) and ibuprofen (50-200mg/kg, orally) produced dose-dependent antinociception, with ED50 values of 27.2 and 100.5mg/kg, respectively. ZC88 in combination with ibuprofen (ZC88+ibuprofen) also induced significant antinociception, and isobolographic analysis revealed a synergistic interaction at 50% effect level. The experimental ED50 (ED50 mix ) of this combination (34.5mg/kg) was significantly lower than the theoretical ED50 (ED50 add ; 63.8mg/kg). Additionally, composite additive curve analysis displayed synergistic interaction at other effect levels. In the formalin test, ZC88 or ibuprofen alone significantly reduced late-phase rather than early-phase pain, with ED50 values of 31.3 and 123.9mg/kg, respectively. Similarly, both isobolographic analysis and composite additive curve analysis revealed synergistic antinociception of ZC88+ibuprofen (40.6mg/kg of ED50 mix vs. 77.6mg/kg of ED50 add ). ZC88 in combination with ibuprofen produces synergistic antinociception in mouse models of somatic and visceral inflammatory pain. Because ZC88+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 ZC88 on ibuprofen-induced antinociception indicates that N-VDCC blocker has potential benefit to treat severe inflammatory pain.