Department of Pain Medicine, The University of Texas MD Anderson Cancer Centre, Houston, TX 77030, USA.
J Physiol. 2011 Sep 15;589(Pt 18):4511-26. doi: 10.1113/jphysiol.2011.215301. Epub 2011 Jul 25.
Spinal application of TNFα induces both allodynia and hyperalgesia, and at least part of the pronociceptive effects of TNFα have been suggested as due to the impaired function of spinal inhibitory neurons (disinhibition). The present study explores the effects of TNFα on the signalling phenotype of spinal GABAergic neurons identified in transgenic mice expressing green fluorescent protein at the glutamic acid decarboxylase 67 (GAD67) promoter. Acute application of TNFα directly inhibits the excitability of a subset of GAD67(+) spinal neurons. TNFα-induced inhibition was dependent on the activation of p38 mitogen-activated protein kinase (MAPK) within these GAD67(+) neurons. TNFα receptor 1 (TNFR1) but not receptor 2 (TNFR2) was identified on spinal GAD67(+) neurons, suggesting that TNFα signals through TNFR1. Voltage-clamp recordings of GAD67(+) neurons indicated that the inhibitory effect of TNFα was through suppression of the hyperpolarization-activated cation current (I(h)). This study defines a novel mechanism of spinal disinhibition mediated by a TNFα-TNFR1-p38 pathway within GABAergic inhibitory interneurons.
TNFα 经脊柱给药可引发痛觉过敏和痛觉超敏，且 TNFα 的至少部分致痛作用被认为是由于脊髓抑制性神经元功能受损（去抑制）所致。本研究旨在探讨 TNFα 对在谷氨酸脱羧酶 67（GAD67）启动子表达绿色荧光蛋白的转基因小鼠中鉴定出的脊髓 GABA 能神经元信号表型的影响。TNFα 的急性给药可直接抑制谷氨酸脱羧酶 67（GAD67）阳性（+）脊髓神经元的兴奋性。TNFα 诱导的抑制作用依赖于这些 GAD67(+)神经元中 p38 丝裂原活化蛋白激酶（MAPK）的激活。在脊髓 GAD67(+)神经元上鉴定出 TNFα 受体 1（TNFR1）而不是受体 2（TNFR2），表明 TNFα 通过 TNFR1 发出信号。GAD67(+)神经元的电压钳记录表明，TNFα 的抑制作用是通过抑制超极化激活阳离子电流（I(h)）实现的。本研究定义了一种新的脊髓去抑制机制，即 TNFα-TNFR1-p38 通路在 GABA 能抑制性中间神经元中的作用机制。
