Strominger N L, Brady R, Gullikson G, Carpenter D O
Albany Medical College, Albany, NY 12208, USA.
Brain Res Bull. 2001 Jun;55(3):445-51. doi: 10.1016/s0361-9230(01)00539-1.
The immunomodulator, imiquimod, has been shown to have antiviral and antitumor properties in animal models. It also has been reported to alter cytokine levels in both animals and humans. However, because imiquimod appeared to be emetic, studies were conducted to determine the degree of sensitivity, and the pathways involved. Subcutaneous administration of > or = 10 mg/kg imiquimod to ferrets elicited emesis with latencies as short as 2'; 12 and 15 mg/kg were optimal doses. Emetic responsiveness was eliminated by complete ablation of the area postrema, but was unaffected by bilateral supradiaphragmatic section of the vagus nerve. This indicates that the emesis is produced by an activation of the chemoreceptor trigger zone B the area postrema. Ferret brain stem slices (450 microm) were preincubated in oxygenated Krebs-Ringer and then mounted in a submerged slice recording chamber. Extracellular recordings of spontaneous and ionophoretically evoked activity of area postrema neurons were obtained for up to 8 h, while the effect of bath-applied imiquimod was determined. Under control conditions, neurons showed a low frequency spontaneous discharge. Introduction of imiquimod (concentration range, 1 x 10(-7) to 5 x 10(-8)M) had no effect on neuronal firing. With ionophoresis of glutamate from an independent micropipette, a brief excitatory response was obtained. We conclude that imiquimod does not directly excite area postrema neurons. It is likely that imiquimod causes synthesis and release of some unknown emetic substance(s), very possibly cytokines.
免疫调节剂咪喹莫特在动物模型中已显示出抗病毒和抗肿瘤特性。据报道，它还会改变动物和人类体内的细胞因子水平。然而，由于咪喹莫特似乎会引起呕吐，因此开展了研究以确定其敏感程度及相关途径。对雪貂皮下注射≥10mg/kg咪喹莫特会引发呕吐，潜伏期短至2分钟；12mg/kg和15mg/kg为最佳剂量。通过完全切除最后区可消除呕吐反应，但双侧膈上迷走神经切断术对此无影响。这表明呕吐是由化学感受器触发区即最后区的激活所引起的。将雪貂脑干切片（450微米）在充氧的 Krebs-Ringer 溶液中预孵育，然后置于浸没式切片记录室中。在长达8小时的时间内记录最后区神经元的自发和离子电渗诱发活动的细胞外记录，同时测定浴加咪喹莫特的效果。在对照条件下，神经元表现出低频自发放电。加入咪喹莫特（浓度范围为1×10⁻⁷至5×10⁻⁸M）对神经元放电无影响。用独立微电极离子电渗谷氨酸可获得短暂的兴奋反应。我们得出结论，咪喹莫特不会直接兴奋最后区神经元。咪喹莫特很可能会导致某种未知催吐物质（很可能是细胞因子）的合成和释放。
