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The interphase of the formalin test

机译:福尔马林测试的中间阶段

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The formalin test still surprises with its biphasic pain-related behavior resulting from a quiescent interphase that does not occur with other algogenic compounds and remains unexplained. The first phase has been attributed to TRPA1-mediated excitation of nociceptors, the second phase to their inflammatory and/or spinal sensitization. We show that the second and interphase require higher formaldehyde concentrations to emerge, and that from 12 mM on calcium influx is induced in TRPA1-deficient sensory neurons as well as in native HEK293T cells. After a short depolarizing and excitatory period in a subset, all wild-type neurons showed a concentration-dependent hyperpolarization, a reduction of voltage-activated sodium currents, and a progressive increase of the input resistance, which, after about 10 min restored the transiently lost excitability, enabling smaller and wider action potentials to be evoked than before formaldehyde (30 mM). The hyperpolarizing effect was absent if extracellular sodium was replaced, and largely prevented by a high but not low concentration of tetrodotoxin. In rat skin in vivo, the spatiotemporal redistribution of injected formalin and the plasma extravasation were studied using Evans blue. The parameters gained were entered into a computational model to predict the activation pattern of primary afferents. The model supports a peripherally generated biphasic response, the time course matching the behavioral results. In conclusion, the interphase is a result of hyperpolarization and transient inactivation by formaldehyde of the surviving neurons; their recovery and the centrifugal spread of formalin in the skin induce a second phase of nociceptive activity before the formalin concentration falls below threshold.
机译:福尔马林测试仍然令人惊讶,其双相疼痛相关行为是由静止相形成的,该相态与其他促生化合物未发生,并且仍无法解释。第一阶段归因于伤害感受器的TRPA1介导的激发,第二阶段归因于其炎症和/或脊椎敏化。我们显示第二阶段和中间阶段需要更高的甲醛浓度才能出现,并且从TRPA1缺失的感觉神经元以及天然HEK293T细胞中诱导的钙内流起12 mM。在一个短暂的去极化和兴奋期后,所有野生型神经元均表现出浓度依赖性超极化,电压激活的钠电流减少和输入电阻逐渐增加,在约10分钟后恢复了瞬时状态失去了兴奋性,因此可以唤起比甲醛(30 mM)之前更小的动作电位。如果细胞外钠被替换,则没有超极化作用,并且高浓度但不是低浓度的河豚毒素在很大程度上防止了这种作用。在体内大鼠皮肤中,使用伊文思蓝研究了注射福尔马林的时空再分布和血浆外渗。获得的参数被输入到计算模型中以预测初级传入的激活模式。该模型支持外围产生的双相响应,时间过程与行为结果匹配。总之,中间相是幸存的神经元的超极化和甲醛瞬时失活的结果。它们的恢复和福尔马林在皮肤中的离心扩散会在福尔马林浓度降至阈值以下之前引发第二阶段的伤害感受活性。

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