Hagenacker T, Lampe M, Schäfers M
Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany.
Department of Neurology, University Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany.
Brain Res. 2014 Apr 4;1557:171-9. doi: 10.1016/j.brainres.2014.02.022. Epub 2014 Feb 18.
Recently, the transient receptor potential (TRP) channels TRPM8 and TRPA1 have been identified as molecular sensors for cold, and it has been suggested that they play a crucial role in allodynia by modulating voltage-gated calcium channel currents (ICa(V)). The aim of this study was to analyze the modulation of ICa(V) by the TRPM8-agonist icilin in vitro and to investigate the analgesic effect of icilin in a neuropathic pain model in vivo. Whole cell patch-clamp recordings were performed on isolated naïve and injured rat dorsal root ganglia (DRG) neurons, and the analgesic efficacy of icilin applied topically to the paws or intrathecally was tested in rats after spinal nerve ligation (SNL). ICa(V) (depolarization from -80 to 0mV) in naïve DRG neurons was reduced dose dependently (0.002-200µM) by icilin (18-80%). Subtype isolation of calcium channels show a marked reduction of L-type channel currents compared to N-type channel currents. The effects of icilin on ICa(V) were not significantly different in non-injured and SNL-injured DRG neurons. In vivo, neither topical (10-200µM) nor intrathecal application of icilin (0.1nM to 1µM) affected tactile allodynia or thermal hyperalgesia after SNL, but it increases cold allodynia 6h after application. We conclude that the icilin-induced modulation of ICa(V) in DRG neurons is unlikely to mediate analgesic effects or contribute directly to the pathogenesis of cold allodynia in the rat SNL model, but it is a potential mechanism for the analgesic effects of icilin in other pain models.
最近，瞬时受体电位（TRP）通道TRPM8和TRPA1已被确定为冷觉分子传感器，有人认为它们通过调节电压门控钙通道电流（ICa(V)）在异常性疼痛中起关键作用。本研究的目的是在体外分析TRPM8激动剂艾考糊精对ICa(V)的调节作用，并在体内神经病理性疼痛模型中研究艾考糊精的镇痛效果。对分离的未损伤和损伤大鼠背根神经节（DRG）神经元进行全细胞膜片钳记录，并在大鼠脊神经结扎（SNL）后测试局部应用于爪部或鞘内注射的艾考糊精的镇痛效果。在未损伤的DRG神经元中，艾考糊精（0.002 - 200µM）使ICa(V)（从-80mV去极化到0mV）呈剂量依赖性降低（18 - 80%）。钙通道亚型分离显示，与N型通道电流相比，L型通道电流显著降低。艾考糊精对ICa(V)的作用在未损伤和SNL损伤的DRG神经元中无显著差异。在体内，SNL后，局部应用（10 - 200µM）或鞘内注射艾考糊精（0.1nM至1µM）均不影响触觉异常性疼痛或热痛觉过敏，但在应用后6小时会增加冷觉异常性疼痛。我们得出结论，艾考糊精诱导的DRG神经元中ICa(V)的调节不太可能介导镇痛作用或直接导致大鼠SNL模型中冷觉异常性疼痛的发病机制，但它是艾考糊精在其他疼痛模型中产生镇痛作用的潜在机制。
